scholarly journals CD4+T Cells Drive Goblet Cell Depletion during Citrobacter rodentium Infection

2013 ◽  
Vol 81 (12) ◽  
pp. 4649-4658 ◽  
Author(s):  
Justin M. Chan ◽  
Ganive Bhinder ◽  
Ho Pan Sham ◽  
Natasha Ryz ◽  
Tina Huang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Goblet Cell ◽  
Gene Knockout ◽  
Mortality Rates ◽  
T Cell Subsets ◽  
Cell Depletion ◽  
Citrobacter Rodentium ◽  
Content Type ◽  
Cell Numbers

ABSTRACTBoth idiopathic and infectious forms of colitis disrupt normal intestinal epithelial cell (IEC) proliferation and differentiation, although the mechanisms involved remain unclear. Recently, we demonstrated that infection by the attaching and effacing murine pathogenCitrobacter rodentiumleads to a significant reduction in colonic goblet cell numbers (goblet cell depletion). This pathology depends on T and/or B cells, asRag1−/−mice do not suffer this depletion during infection, instead suffering high mortality rates. To address the immune mechanisms involved, we reconstitutedRag−/−mice with either CD4+or CD8+T cells. Both T cell subsets increasedRag1−/−mouse survival during infection, with mice that received CD8+T cells developing colonic ulcers but not goblet cell depletion. In contrast, mice that received CD4+T cells showed goblet cell depletion in concert with exaggerated IEC proliferation. To define the possible involvement of T cell-derived cytokines, we infected gamma interferon receptor gene knockout (IFN-γR−/−) mice and wild-type mice given interleukin 17A (IL-17A) neutralizing antibodies and found that IFN-γ signaling was required for both goblet cell depletion and increased IEC proliferation. Immunostaining revealed thatC. rodentiumcells preferentially localized to nonhyperplastic crypts containing numerous goblet cells, whereas hyperplastic, goblet cell-depleted crypts appeared protected from infection. To address whether goblet cell depletion benefits theC. rodentium-infected host, we increased goblet cell numbers using the γ-secretase inhibitor dibenzazepine (DBZ), which resulted in greatly increased pathogen burdens and mortality rates. These results demonstrate that goblet cell depletion reflects host immunomodulation of IEC homeostasis and reflects a novel host defense mechanism against mucosal-adherent pathogens.

NaïVe T Cell Depletion of PBSC Grafts Results in Very Low Rates of Chronic Gvhd and High Survival

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 668-668
Author(s):  
Marie Bleakley ◽  
Ted A. Gooley ◽  
Barbara Hilzinger ◽  
Stanley R Riddell ◽  
Warren D Shlomchik
Keyword(s):  
T Cells ◽  
T Cell ◽  
Acute Leukemia ◽  
Chronic Gvhd ◽  
Hematopoietic Cell ◽  
T Cell Subsets ◽  
Cell Depletion ◽  
Effector Memory ◽  
Phase Ii Trials ◽  
T Cell Depletion

Abstract Background Graft-versus-host disease (GVHD) frequently causes morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT) as a result of organ damage and infections. In HLA-identical HCT, GVHD results from recognition by donor T cells of minor histocompatibility (H) antigens on recipient tissues. Complete T cell depletion (TCD) of donor hematopoietic cell products is more effective than pharmacologic immunosuppression for preventing GVHD, but is complicated by delayed immune reconstitution and consequent life-threatening infections.Approaches to HCT which preferentially deplete the T cells that primarily cause GVHD and preserve pathogen-specific T cells may improve HCT outcomes. Mature CD3+ CD8+ and CD3+ CD4+ T cells can be classified into CD45RA+ CD62L+ naïve (TN) and CD45RO+ memory (TM) subsets, the latter of which includes effector memory (TEM) and central memory (TCM) cells. Murine studies in which allogeneic TCD bone marrow (BM) is transplanted with purified T cells from individual T cell subsets to irradiated minor H antigen disparate recipients have demonstrated that the most severe GVHD results from transplanting T cells of the TN subset. Purified TCM causes mild GVHD and TEM do not cause detectable GVHD and can transfer immunity to pathogens.In vitro studies have similarly demonstrated that human donor CD8+ T cells specific for recipient minor H antigens are found predominantly within the TN cell subset, suggesting selective TN cell depletion may alter the GVHD incidence and/or severity in human HCT. Methods and results We developed an effective process for engineering human peripheral blood stem cell (PBSC) grafts that depletes CD45RA+ TN cells and retains CD34+ stem cells and functional CD45RO+ TM cells specific for a broad range of opportunistic pathogens (Bleakley BBMT 2014). We are conducting clinical trials to evaluate the selective depletion of TN cells from HLA-matched allogeneic PBSC grafts for the prevention of GVHD in patients with acute leukemia, the first of which has been published (Bleakley JCI 2015, N=35). Seventy patients have now been treated on three consecutive phase II trials. The median age was 34 years (1-56 years), 56% of patients had a diagnosis of ALL, 46% had previously relapsed or had detectable disease (MRD or relapse) at the time of HCT, and 23% had unrelated donor (URD) grafts. Intensive myeloablative, TBI-containing (13.2Gy) conditioning was used for 63 patients, whilst 7 patients received a medium intensity 'midi' preparative regimen, including 4Gy of TBI. The TN-depletion procedure was successfully performed on URD PBSC products shipped overnight from donor centers throughout the US, as well as on MRD PBSC collected at our centers. Reliable engraftment with high-level donor chimerism was observed in recipients of 'midi' as well as intensive myeloablative conditioning. The 2-year estimates of overall survival, disease-free survival, survival free of relapse and chronic GVHD (CRFS) and survival free of relapse, grade II-IV acute GVHD, and chronic GVHD (GRFS) are 79%, 73%, 69% and 63% respectively. Median follow-up among survivors is 26 months. The frequency and severity of chronic GVHD is remarkably low (5%) compared to historical rates of 40-60% chronic GVHD in HLA-matched PBSC transplantation with conventional calcineurin inhibitor-based immunosuppression. Relapse and non-relapse mortality (NRM) are acceptably low at 19% and 8%, respectively. No NRM occurred in patients <40 years. Updated results will be presented. Conclusions The outcomes of recipients of TN-depleted PBSC grafts compare very favorably to published results of HCT for patients with acute leukemia. For example, the 69% incidence of CRFS at 2 years in TN-depleted recipients compares with reported 2-year GRFS rates of 37% and 17% in recipients of allogeneic PBSC from HLA-matched related donors with or without ATG (Kroger et al. NEJM 2016). Our results suggest that TN-depletion of PBSC grafts may reduce the risk of chronic GVHD without negatively impacting other important HCT outcomes. Disclosures Riddell: Juno Therapeutics: Equity Ownership, Patents & Royalties, Research Funding; Cell Medica: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria.

scholarly journals Protein Energy Malnutrition during Vaccination Has Limited Influence on Vaccine Efficacy but Abolishes Immunity if Administered during Mycobacterium tuberculosis Infection

2015 ◽  
Vol 83 (5) ◽  
pp. 2118-2126 ◽  
Author(s):  
Truc Hoang ◽  
Else Marie Agger ◽  
Joseph P. Cassidy ◽  
Jan P. Christensen ◽  
Peter Andersen
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Cd4 T Cells ◽  
Protein Energy Malnutrition ◽  
T Cell Subsets ◽  
Content Type ◽  
Protein Energy ◽  
Tnf Α ◽  
Ifn Γ

Protein energy malnutrition (PEM) increases susceptibility to infectious diseases, including tuberculosis (TB), but it is not clear how PEM influences vaccine-promoted immunity to TB. We demonstrate that PEM during low-level steady-state TB infection in a mouse model results in rapid relapse ofMycobacterium tuberculosis, as well as increased pathology, in bothMycobacterium bovisBCG-vaccinated and unvaccinated animals. PEM did not change the overall numbers of CD4 T cells in BCG-vaccinated animals but resulted in an almost complete loss of antigen-specific cytokine production. Furthermore, there was a change in cytokine expression characterized by a gradual loss of multifunctional antigen-specific CD4 T cells and an increased proportion of effector cells expressing gamma interferon and tumor necrosis factor alpha (IFN-γ+TNF-α+and IFN-γ+cells). PEM duringM. tuberculosisinfection completely blocked the protection afforded by the H56-CAF01 subunit vaccine, and this was associated with a very substantial loss of the interleukin-2-positive memory CD4 T cells promoted by this vaccine. Similarly, PEM during the vaccination phase markedly reduced the H56-CAF01 vaccine response, influencing all cytokine-producing CD4 T cell subsets, with the exception of CD4 T cells positive for TNF-α only. Importantly, this impairment was reversible and resupplementation of protein during infection rescued both the vaccine-promoted T cell response and the protective effect of the vaccine againstM. tuberculosisinfection.

scholarly journals Loss of Immunization-Induced Epitope-Specific CD4 T-Cell Response following Anaplasma marginale Infection Requires Presence of the T-Cell Epitope on the Pathogen and Is Not Associated with an Increase in Lymphocytes Expressing Known Regulatory Cell Phenotypes

2015 ◽  
Vol 22 (7) ◽  
pp. 742-753 ◽  
Author(s):  
Wendy C. Brown ◽  
Joshua E. Turse ◽  
Paulraj K. Lawrence ◽  
Wendell C. Johnson ◽  
Glen A. Scoles ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Response ◽  
Cell Epitope ◽  
T Cell Response ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
Γδ T Cell ◽  
Content Type ◽  
Cell Responses

ABSTRACTWe have shown that in cattle previously immunized with outer membrane proteins, infection withAnaplasma marginaleinduces a functionally exhausted CD4 T-cell response to theA. marginaleimmunogen. Furthermore, T-cell responses following infection in nonimmunized cattle had a delayed onset and were sporadic and transient during persistent infection. The induction of an exhausted T-cell response following infection presumably facilitates pathogen persistence. In the current study, we hypothesized that the loss of epitope-specific T-cell responses requires the presence of the immunizing epitope on the pathogen, and T-cell dysfunction correlates with the appearance of regulatory T cells. In limited studies in cattle, regulatory T cells have been shown to belong to γδ T-cell subsets rather than be CD4 T cells expressing forkhead box protein P3 (FoxP3). Cattle expressing the DRB3*1101 haplotype were immunized with a truncatedA. marginalemajor surface protein (MSP) 1a that contains a DRB3*1101-restricted CD4 T-cell epitope, F2-5B. Cattle either remained unchallenged or were challenged withA. marginalebacteria that express the epitope or withA. marginalesubsp.centralethat do not. Peripheral blood and spleen mononuclear cells were monitored for MSP1a epitope F2-5B-specfic T-cell proliferative responses and were stained for γδ T-cell subsets or CD4+CD25+FoxP3+T cells before and during infection. As hypothesized, the induction of T-cell exhaustion occurred only following infection withA. marginale, which did not correlate with an increase in either CD4+CD25+FoxP3+T cells or any γδ T-cell subset examined.

scholarly journals The Hitchhiker Guide to CD4+ T-Cell Depletion in Lentiviral Infection. A Critical Review of the Dynamics of the CD4+ T Cells in SIV and HIV Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Quentin Le Hingrat ◽  
Irini Sereti ◽  
Alan L. Landay ◽  
Ivona Pandrea ◽  
Cristian Apetrei
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Replication ◽  
Cd4 T Cells ◽  
Microbial Translocation ◽  
T Cell Subsets ◽  
Cell Depletion ◽  
Cell Recovery ◽  
T Cell Depletion ◽  
Siv Infection

CD4+ T-cell depletion is pathognomonic for AIDS in both HIV and simian immunodeficiency virus (SIV) infections. It occurs early, is massive at mucosal sites, and is not entirely reverted by antiretroviral therapy (ART), particularly if initiated when T-cell functions are compromised. HIV/SIV infect and kill activated CCR5-expressing memory and effector CD4+ T-cells from the intestinal lamina propria. Acute CD4+ T-cell depletion is substantial in progressive, nonprogressive and controlled infections. Clinical outcome is predicted by the mucosal CD4+ T-cell recovery during chronic infection, with no recovery occurring in rapid progressors, and partial, transient recovery, the degree of which depends on the virus control, in normal and long-term progressors. The nonprogressive infection of African nonhuman primate SIV hosts is characterized by partial mucosal CD4+ T-cell restoration, despite high viral replication. Complete, albeit very slow, recovery of mucosal CD4+ T-cells occurs in controllers. Early ART does not prevent acute mucosal CD4+ T-cell depletion, yet it greatly improves their restoration, sometimes to preinfection levels. Comparative studies of the different models of SIV infection support a critical role of immune activation/inflammation (IA/INFL), in addition to viral replication, in CD4+ T-cell depletion, with immune restoration occurring only when these parameters are kept at bay. CD4+ T-cell depletion is persistent, and the recovery is very slow, even when both the virus and IA/INFL are completely controlled. Nevertheless, partial mucosal CD4+ T-cell recovery is sufficient for a healthy life in natural hosts. Cell death and loss of CD4+ T-cell subsets critical for gut health contribute to mucosal inflammation and enteropathy, which weaken the mucosal barrier, leading to microbial translocation, a major driver of IA/INFL. In turn, IA/INFL trigger CD4+ T-cells to become either viral targets or apoptotic, fueling their loss. CD4+ T-cell depletion also drives opportunistic infections, cancers, and comorbidities. It is thus critical to preserve CD4+ T cells (through early ART) during HIV/SIV infection. Even in early-treated subjects, residual IA/INFL can persist, preventing/delaying CD4+ T-cell restoration. New therapeutic strategies limiting mucosal pathology, microbial translocation and IA/INFL, to improve CD4+ T-cell recovery and the overall HIV prognosis are needed, and SIV models are extensively used to this goal.

scholarly journals Tigit Expression Defines a Subset of Activated Treg Cells with Prognostic Relevance in Follicular Lymphoma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1590-1590 ◽  
Author(s):  
Zhi-Zhang Yang ◽  
Hyo Jin Kim ◽  
Shahrzad Jalali ◽  
Hongyan Wu ◽  
Tammy Price-Troska ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Follicular Lymphoma ◽  
Research Funding ◽  
Memory T Cells ◽  
Treg Cells ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Cell Numbers ◽  
Treg Subset

Abstract T cell Ig and ITIM domain (TIGIT) is an immune checkpoint molecule that is expressed on a variety of cell types including NK cells, effector and memory T cells, and Treg cells. Upon ligation with CD155, TIGIT delivers an inhibitory signal and negatively regulates anti-tumor responses. While important in normal T-cell biology, the pathological significance of TIGIT expression and function in the tumor microenvironment of the patients with follicular lymphoma (FL) is largely unknown. The present study sought to phenotypically and functionally characterize TIGIT+ T cell subsets in FL. While its expression is not detected on resting T cells in peripheral blood, we found that TIGIT is highly expressed on intratumoral T cells from FL. Treatment with cytokines such as IL-4 and TGF-β downregulated TIGIT expression on T cells. We found that TIGIT is predominantly expressed on effector memory T cells (TEM) with an activation/exhausted phenotype, and TIGIT+ T cells have higher expression levels of CD69 and PD-1 when compared to TIGIT- T cells. Functionally, TIGIT+ T cells displayed reduced capacity of cell proliferation and cytokine production (IFN-γ and IL-2). Using mass cytometry (CyTOF), we observed that TIGIT is abundantly expressed on some intratumoral Treg (CD4+CD25+Foxp3+) cells, while other Treg cells lack TIGIT expression in FL, forming two subsets of Treg cells: CD4+CD25+TIGIT+ and CD4+CD25+TIGIT-. These two subsets are phenotypically distinct in that CD25+TIGIT+ cells exhibited increased expression of activation/costimulatory markers such as CD69, CD27 and CD28 compared to CD25+TIGIT-, suggesting an activated Treg subset of CD25+TIGIT+ cells. This CD25+TIGIT+ subset had increased suppressive function and could more effectively inhibit activation and proliferation of CD8+ T cells than CD25+TIGIT- cells. Furthermore, we found that lymphoma B cells promoted the development of TIGIT-expressing T cells as TGF-β-mediated downregulation of TIGIT on T cells was inhibited when CD19+ lymphoma cells were present. Using a cohort of 31 FL patients, we found that intratumoral TIGIT-expressing T cells were associated with a favorable prognosis. Patients with TIGIT+ T cell numbers greater than 50% had better overall survival than patients with TIGIT+ T cell numbers less than 50%. Taken together, our results reveal a role of TIGIT in defining Treg cell subsets with different immune function and TIGIT expression may be useful in predicting patient outcome in FL. Disclosures Ansell: Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; Pfizer: Research Funding; Seattle Genetics: Research Funding; Celldex: Research Funding; Regeneron: Research Funding; LAM Therapeutics: Research Funding; Trillium: Research Funding; Affimed: Research Funding; Merck & Co: Research Funding.

scholarly journals Tpl2 Promotes Innate Cell Recruitment and Effector T Cell Differentiation To Limit Citrobacter rodentium Burden and Dissemination

2017 ◽  
Vol 85 (10) ◽  
Author(s):  
Nicole V. Acuff ◽  
Xin Li ◽  
Krishna Latha ◽  
Tamas Nagy ◽  
Wendy T. Watford
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Immune Cell ◽  
Cd4 T Cell ◽  
Citrobacter Rodentium ◽  
Wild Type ◽  
Content Type ◽  
Cell Recruitment ◽  
Ifn Γ

ABSTRACT Tumor progression locus 2 (Tpl2) is a serine-threonine kinase that regulates Th1 differentiation, secretion of the inflammatory cytokine gamma interferon (IFN-γ), and host defense against the intracellular pathogens Toxoplasma gondii, Listeria monocytogenes, and Mycobacterium tuberculosis. However, relatively little is known about the contribution of Tpl2 to Th17 differentiation and immune cell function during infection with an extracellular pathogen. The goal of this study was to determine whether Tpl2 influences the immune response generated to the extracellular bacterium Citrobacter rodentium, which induces a mixed Th1 and Th17 response. During peak infection with C. rodentium, Tpl2 −/− mice experienced greater bacterial burdens with evidence of dissemination to the liver and spleen but ultimately cleared the bacteria within 3 weeks postinfection, similar to the findings for wild-type mice. Tpl2 −/− mice also recruited fewer neutrophils and monocytes to the colon during peak infection, which correlated with increased bacterial burdens. In mixed bone marrow chimeras, Tpl2 was shown to play a T cell-intrinsic role in promoting both IFN-γ and interleukin-17A production during infection with C. rodentium. However, upon CD4 T cell transfer into Rag −/− mice, Tpl2 −/− CD4 T cells were as protective as wild-type CD4 T cells against the dissemination of bacteria and mortality. These data indicate that the enhanced bacterial burdens in Tpl2 −/− mice are not caused primarily by impairments in CD4 T cell function but result from defects in innate immune cell recruitment and function.

scholarly journals Recruitment of Neutrophils Mediated by Vγ2 γδ T Cells Deteriorates Liver Fibrosis Induced by Schistosoma japonicum Infection in C57BL/6 Mice

2017 ◽  
Vol 85 (8) ◽  
Author(s):  
Li Zheng ◽  
Yuan Hu ◽  
Yanjuan Wang ◽  
Xibao Huang ◽  
Yuxin Xu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Liver Fibrosis ◽  
Schistosoma Japonicum ◽  
Γδ T Cells ◽  
T Cell Subsets ◽  
Interleukin 17 ◽  
Content Type ◽  
Ifn Γ

ABSTRACT Conventional adaptive T cell responses contribute to the pathogenesis of Schistosoma japonicum infection, leading to liver fibrosis. However, the role of gamma-delta (γδ) T cells in this disease is less clear. γδ T cells are known to secrete interleukin-17 (IL-17) in response to infection, exerting either protective or pathogenic functions. In the present study, mice infected with S. japonicum are used to characterize the role of γδ T cells. Combined with the infection of S. japonicum, an extremely significant increase in the percentage of neutrophils in the CD45+ cells was detected (from approximately 2.45% to 46.10% in blood and from 0.18% to 7.34% in spleen). Further analysis identified two different γδ T cell subsets that have different functions in the formation of granulomas in S. japonicum-infected mice. The Vγ1 T cells secrete gamma interferon (IFN-γ) only, while the Vγ2 T cells secrete both IL-17A and IFN-γ. Both subtypes lose the ability to secrete cytokine during the late stage of infection (12 weeks postinfection). When we depleted the Vγ2 T cells in infected mice, the percentage of neutrophils in blood and spleen decreased significantly, the liver fibrosis in the granulomas was reduced, and the level of IL-17A in the serum decreased (P < 0.05). These results suggest that during S. japonicum infection, Vγ2 T cells can recruit neutrophils and aggravate liver fibrosis by secreting IL-17A. This is the first report that a subset of γδ T cells plays a partial role in the pathological process of schistosome infection.

Minimal Residual Disease (MRD) and T/NK Cell Dynamics during Fludarabine, Cyclophosphamide Plus Rituximab (FCR) Followed by Fludarabine Plus Rituximab (FR) and Remission Maintenance Therapy with Rituximab in Previously Untreated B-Chronic Lymphocytic Leukemia (B-CLL): Riskfactor Stratification in the Chairos Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3175-3175 ◽  
Author(s):  
Alexander Egle ◽  
Lukas Weiss ◽  
Franz Gassner ◽  
Gudrun Russ ◽  
Lisa Pleyer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Maintenance Therapy ◽  
Nk Cell ◽  
T Cell Subsets ◽  
Induction Treatment ◽  
Cell Dynamics ◽  
Mutation Status ◽  
Cell Numbers ◽  
Rituximab Maintenance

Abstract Based on the efficacy of Fludarabine, Cyclophosphamide plus Rituximab (FCR) as first-line therapy for chronic lymphocytic leukemia (CLL), we conducted a non-randomized multi-center phase II trial with early brief intensive induction with FCR for 3 cycles followed by fludarabine/rituximab for 3 cycles. In addition patients received a 2 year 3-monthly rituximab maintenance regimen. The trial recruited 42 patients. Clinical baseline data, clinical response results and toxicity of a planned first interim analysis were reported previously (Egle et al, ASH 2007). We now present the data from flow cytometric minimal residual disease (MRD) monitoring during the study in combination with the performed risk factor analyses and report on the findings of detailed analysis of T-cell and NK cell dynamics during the induction phase of the trial. From the previously reported high number of CRs (94% after complete 6 cycle induction) 64% were MRD negative by flow cytometric definition (less than 10−3 G/L CLL cells). All non CR patients were correctly called as MRD positive. Less than 0.1 G/L CLL cells after 3 cycles of FCR identified all patients achieving MDR negativity after the complete induction regimen. CD30 risk, as well as age, FISH cytogenetic analysis and analysis of IgVH mutation status were analysed for their impact on MRD dynamics. We could not find any difference in MRD responses between CD38 high and low risk groups or between age groups (&gt; and &lt;65a). Neither did abberations found in FISH cytogenetics predict the MRD responses and all CLL patients harboring an 11q deletion achieved MRD negativity. Interestingly, we found the only predictive factor to be the IgVH mutation status with 15 unmutated CLL patients significantly less likely to achieve MRD negativity after induction treatment (p=0,025). Especially, three patients with rearranged IgVH 3–21 did poorly, suggesting that these patients may need a different therapeutic approach. Six months of Rituximab maintenance therapy were able to convert 37% of patients from MRD positive state after remission induction to a MRD negative state. T and NK cell numbers and ratios were followed during therapy. In addition T cell subsets and their CD38 expression status were analysed. While absolute T and NK/NKT cell numbers decreased dramatically during treatment (CD4 and CD8 cell numbers decreased to medians of less than 100/μl after 6 cycles of induction treatment), a count of less than 200 CD4 cells/μl after 3 cycles of FCR was found to be predictive of MRD negativity. In addition, we observed an earlier recovery of NK and NKT cells after the end of induction treatment leading to an inverted NK(T) to T cell ratio early during maintenance treatment. This may have implications for NK-dependent ADCC during rituximab maintenance therapy. Regarding the CD4 and CD8 compartment we observed in addition to the reduction in absolute numbers a marked shift of T cell subsets. Naïve T cells were more completely depleted by FCR/FR treatment than T cells from the memory compartment, with central memory (CM) CD4 cells increasing from a median of 49% to 79%. This was less pronounced in the CD8 compartment. CD38 expression on T cells was monitored, because our group found that this was predictive of CLL course (Tinhofer Blood 2006). Interestingly we found a marked increase of the proportional representation of CD38+ CD8 and CD4 T cells in the T cell compartment with a more pronounced effect observed in the CD8 compartment. CD8 T cell counts were also quicker to recover during rituximab maintenance therapy. While these data point to essential caveats regarding the immunosuppressive toxicity of the treatment, they may also point to a window of opportunity regarding the modification of T cell responses during the phase of immune reconstitution after FCR/FR therapy. In conclusion we find that only IgVH mutation status was predictive of achievement of MRD negativity and we could show significant skewing of T cell and NK(T) cell subsets during chemoimmunotherapy. A better understanding of these T/NK cell dynamics may lead to the development of improved targeting of the immune recovery phase after chemotherapy using immunomodulating maintenance strategies.

scholarly journals Central Role for B Lymphocytes and CD4+ T Cells in Immunity to Infection by the Attaching and Effacing Pathogen Citrobacter rodentium

2003 ◽  
Vol 71 (9) ◽  
pp. 5077-5086 ◽  
Author(s):  
Cameron P. Simmons ◽  
Simon Clare ◽  
Marjan Ghaem-Maghami ◽  
Tania K. Uren ◽  
Joanna Rankin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Lymphocytes ◽  
Adoptive Transfer ◽  
Acute Infection ◽  
Bacterial Pathogen ◽  
T Cell Subsets ◽  
Citrobacter Rodentium ◽  
Severe Colitis

ABSTRACT Citrobacter rodentium, an attaching-effacing bacterial pathogen, establishes an acute infection of the murine colonic epithelium and induces a mild colitis in immunocompetent mice. This study describes the role of T-cell subsets and B lymphocytes in immunity to C. rodentium. C57Bl/6 mice orally infected with C. rodentium resolved infection within 3 to 4 weeks. Conversely, systemic and colonic tissues of RAG1−/− mice orally infected with C. rodentium contained high and sustained pathogen loads, and in the colon this resulted in a severe colitis. C57Bl/6 mice depleted of CD4+ T cells, but not CD8+ T cells, were highly susceptible to infection and also developed severe colitis. Mice depleted of CD4+ T cells also had diminished immunoglobulin G (IgG) and IgA antibody responses to two C. rodentium virulence-associated determinants, i.e., EspA and intimin, despite having a massively increased pathogen burden. Mice with an intact T-cell compartment, but lacking B cells (μMT mice), were highly susceptible to C. rodentium infection. Systemic immunity, but not mucosal immunity, could be restored by adoptive transfer of convalescent immune sera to infected μMT mice. Adoptive transfer of immune B cells, but not naïve B cells, provided highly variable immunity to recipient μMT mice. The results suggest that B-cell-mediated immune responses are central to resolution of a C. rodentium infection but that the mechanism through which this occurs requires further investigation. These data are relevant to understanding immunity to enteric attaching and effacing bacterial pathogens of humans.

scholarly journals Citrobacter rodentium Induces Tissue-Resident Memory CD4+ T Cells

2019 ◽  
Vol 87 (7) ◽  
Author(s):  
S. Bishu ◽  
G. Hou ◽  
M. El Zaatari ◽  
S. R. Bishu ◽  
D. Popke ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Host Defense ◽  
Citrobacter Rodentium ◽  
Content Type ◽  
Tumor Growth Factor ◽  
Reporter Mice ◽  
Secondary Infections ◽  
Resident Memory T Cells ◽  
Memory Cd4 T Cells

ABSTRACT Tissue-resident memory T cells (TRM cells) are a novel population of tissue-restricted antigen-specific T cells. TRM cells are induced by pathogens and promote host defense against secondary infections. Although TRM cells cannot be detected in circulation, they are the major memory CD4+ and CD8+ T-cell population in tissues in mice and humans. Murine models of CD8+ TRM cells have shown that CD8+ TRM cells maintain tissue residency via CD69 and though tumor growth factor β-dependent induction of CD103. In contrast to CD8+ TRM cells, there are few models of CD4+ TRM cells. Thus, much less is known about the factors regulating the induction, maintenance, and host defense functions of CD4+ TRM cells. Citrobacter rodentium is known to induce IL-17+ and IL-22+ CD4+ T cells (Th17 and Th22 cells, respectively). Moreover, data from IL-22 reporter mice show that most IL-22+ cells in the colon 3 months after C. rodentium infection are CD4+ T cells. This collectively suggests that C. rodentium may induce CD4+ TRM cells. Here, we demonstrate that C. rodentium induces a population of IL-17A+ CD4+ T cells that are tissue restricted and antigen specific, thus meeting the criteria of CD4+ TRM cells. These cells expand and are a major source of IL-22 during secondary C. rodentium infection, even before the T-cell phase of the host response in primary infection. Finally, using FTY 720, which depletes circulating naive and effector T cells but not tissue-restricted T cells, we show that these CD4+ TRM cells can promote host defense.

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