scholarly journals A role for CD4 helper cells in HIV control and progression

2021 ◽  
Author(s):  
Igor M Rouzine
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Alternative Explanation ◽  
Arms Race ◽  
Cd4 Cells ◽  
Viral Dissemination ◽  
Small Minority ◽  
Helper Cells ◽  
Untreated Individuals

It remains unclear why HIV persists in most untreated individuals, and why a small minority of individuals can control the virus, either spontaneously or after an early treatment. The present work motivated by the striking differences in the functional avidity of CD4 T cells discovered between patient cohorts in a recent study [1] offers an experimentally–testable mathematical model that explains the diverse outcome of infection. The model predicts an arms race between viral dissemination and the proliferation of HIV-specific CD4 helper cells leading to one of two states: a low-viremia state or a high-viremia state. Helper CD4 cells with a higher avidity favor virus control. The parameter segregating spontaneous and post-treatment controllers is the infectivity asymmetry between activated and resting CD4 T cells. The predictions are found to be consistent with the data from [1] and with data on the avidity CD8 T cells [2]. I also analyze the alternative explanation of T cell exhaustion previously proposed to explain the diverse patient cohorts and demonstrate that it does not explain these and some other experimental data.

scholarly journals Tumor Protective Activity of CD4+ but Not of CD8+ T Cells in DNA-Vaccinated Mice Challenged with bcr-abl-Transformed Cells

2013 ◽  
Vol 2013 ◽  
pp. 1-5 ◽  
Author(s):  
Martina Petráčková ◽  
Vincent Lučanský ◽  
Vladimír Vonka
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Fusion Gene ◽  
Subcutaneous Administration ◽  
Vaccine Dose ◽  
Transformed Cells ◽  
Present System ◽  
Cd4 Cells ◽  
Almost All

In the recent past, it has repeatedly been reported that CD4 cells play an important role in the immunology of chronic myeloid leukaemia. It was therefore of interest to test their activity in an animal model using bcr-abl-transformed cells. BALB/c mice were four times immunized with a DNA vaccine carrying the bcr-abl fusion gene. Two weeks after the last vaccine dose, the animals were challenged with syngeneic bcr-abl-transformed 12B1 cells which form solid tumors after subcutaneous administration. At the time of challenge, animals were treated with antibodies against the CD8+ T cells or CD4+ T cells. The efficacy of the depletion was monitored and found highly effective. All nonimmunized animals developed tumors. All animals untreated with the antibodies as well as those in which CD8+ T cells had been depleted, were fully protected against the challenge. On the other hand, almost all mice treated with anti-CD4+ antibody developed tumors. These results strongly suggested that the CD4+ T cells acted as effectors in the present system.

Immunologic Recovery after Nonmyeloablative (NM) Conditioning: A Comparison between Related Versus Unrelated Donor Hematopoietic Cell Transplantation (HCT).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1402-1402 ◽  
Author(s):  
Frederic Baron ◽  
M. Maris ◽  
J. Storek ◽  
M. Metcalf ◽  
K. White ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Cd8 T Cells ◽  
T Helper Cells ◽  
Cd4 T Cells ◽  
Immune Reconstitution ◽  
Infectious Complications ◽  
T Helper ◽  
Helper Cells ◽  
Cmv Reactivation

Abstract Background. After NM conditioning, recipients of peripheral blood stem cells (PBSC) from HLA-identical siblings (MRD) have persistent recipient-derived immunity leading to lower incidence of early infectious complications in comparison with patients (pts) given myeloablative conditioning (Exp Hematol31: 941, 2003). Because of greater genetic disparities, intensity and duration of postgrafting immunosuppression (IS) have been increased in pts given PBSC from HLA-matched unrelated donors (URD), in order to both promote engraftment and decrease risk of GVHD. This study was done to determine how this increased/extended postgrafting IS affected immune recovery and infectious complications. Methods. We compared immunologic recovery in 51 pts given PBSC from MRD (n=51) and 43 pts given grafts from URD after 2 Gy TBI +/− fludarabine. Postgrafting IS concisted of mycophenolate mofetil (MMF, given TID for 40 days followed by a 56 day taper in URD recipients, and BID for 28 days in MRD recipients) and cyclosporin. The counts of blood mononuclear cell subsets were assessed by flow cytometry; frequency of CMV-specific CD4 T-helper cells among CMV seropositive pts or CMV-seronegative pts with CMV-seropositive donors was determined by lymphoproliferation (LPR), limiting-dilution assays (LDA), and intracellular interferon-gamma (IF) production (ICC). Analyses were performed on days 30, 80, 180 and 365 after HCT. Results. On day 30 after HCT, URD recipients had lower counts of total B-cells (P=.02), naive B-cells (P=.03), memory B-cells (P=.01), CD4 T-cells (P=.06), naive CD4 T-cells (P=.05), memory CD4 T-cells (P=.003), CD8 T-cells (P=.0004), naive CD8 T-cells (P=.08) and memory CD8 T-cells (P=.006) than MRD recipients. However, the counts of mononuclear cell subsets were similar in URD and MRD recipients from day 30 to day 365 after HCT. Similarly, the frequency of CMV-specific T-helper cells was significantly lower in URD than in MRD recipients on day 30 after HCT as determined by LPR (median CPM 17 versus 92 per 1000 CD4 T-cells, P=.02), LDA (median 22307 versus 73251 CMV-CD4 T-helper cells per L, P=.7) and ICC (median 0.26% versus 0.93% CD4 cells positive for IF, P=.02). This delay in CMV-specific immune reconstitution translated into increased frequency of CMV-reactivation (and increased use of preemptive antiviral therapy [PET]) among CMV-seropositive pts or CMV-seronegative pts with CMV seropositive donors given URD grafts (63%) compared with MRD (33%) recipients (P=.02) the first 100 days after HCT. This did not lead to increased CMV disease among URD recipients (1 episode) compared with MRD recipients (1 episode), demonstrating that PET was similarly effective in preventing CMV diseases in both groups. After day 100, there were no statistically significant differences in immune reconstitution parameters. Incidence figures for non-CMV viral infections, bacteremias, and invasive fungal infections were not significantly different between the 2 groups. A multivariate analysis assessing pre-transplant and post-transplant factors associated with immunologic recovery after NM conditioning will be presented. Conclusions. Despite similar NM conditioning regimens, immunologic recovery was delayed among URD recipients in comparison to MRD recipients, probably because of increased/extended postgrafting IS. This led to increased incidence of CMV reactivation among URD recipients. CMV infection and immune reconstitution pattern appear similar to those seen after myeloablative PBSC transplantation.

CD8+ but Not CD4+ T Cells Require Cognate Interactions with Target Tissues To Mediate GVHD across Only Minor H Antigens but CD4+ and CD8+ T Cells Both Require Direct Leukemic Contact for GVL.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 580-580 ◽  
Author(s):  
Warren D. Shlomchik ◽  
Catherine Matte ◽  
Jinli Liu ◽  
Dhanpat Jain ◽  
Jennifer McNiff
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Severe Disease ◽  
Target Tissue ◽  
Cd4 Cells ◽  
Mhc I ◽  
Cd8 Cells ◽  
Mhcii Expression

Abstract There has been debate as to whether CD4+ or CD8+ T cells require direct cognate interactions with their tissue targets to mediate GVHD. In one report, GVHD mediated by CD4 or CD8 cells did not require target tissue MHCI or MHCII expression in MHC-disparate models (Teshima, et al 2002). However, GVHD lethality may have been due to cytokines produced by high-frequency alloreactive T cells primed by MHC-disparate host APCs. In contrast, MHC-matched, multiple minor H antigen (miHA) disparate GVHD mediated by CD4 or CD8 cells has been reported to be reduced or absent in host → donor chimeric recipients of a second transplant with donor BM and T cells. In this case, host antigen was restricted to hematopoietic cells and the authors concluded that tissue miHA expression must be required (Korngold and Sprent, 1982; Jones et al, 2003). However these experiments did not address whether T cells directly interacted with MHC on target tissues. Rather they demonstrated that a continuing source of host antigen was essential. To resolve this we created bone marrow chimeras in which hematopoiesis was wild type (wt) while the parenchyma was either MHC I- (B6→B6 beta-2-microglobulin−/− (β2M−/−)) or MHC II− (B6→B6 IAb−/−) and used these chimeras as recipients in GVHD-inducing second transplants. We found that B6→B6β2M−/− chimeras were completely resistant clinically and pathologically to CD8-mediated GVHD induced by a second transplant with C3H.SW (H-2b) BM and CD8+ T cells whereas control B6→B6 chimeras developed severe disease. Thus, CD8 cells require direct cognate interactions with target host tissues to induce MHC-matched, miHA disparate GVHD. In contrast, B6→B6 IAb−/− chimeras developed similar clinical and histologic GVHD (liver, ear, skin and bowel) as did control B6→B6 chimeras when retransplanted with 129/J (H-2b) bone marrow and purified CD4+ T cells. Notably we observed lymphocytic infiltrates in involved organs. Therefore, CD4 cells can mediate tissue damage without directly recognizing alloantigen presented by MHCII on target epithelial cells. This suggests an indirect mechanism, perhaps mediated by T cell release of factors after stimulation in tissues by donor-derived APCs presenting host antigens. Alternatively, donor CD4 cells may activate miHA-bearing macrophages to release inflammatory mediators. To investigate the requirement for cognate recognition in GVL, we created murine CML via retroviral-mediated bcr-abl (p210) transduction of bone marrow from wt B6, B6 IAb−/− and B6 β2M−/− mice. Using the C3H.SW→B6 and 129→B6 GVHD models we found that both CD8-and CD4-mediated GVL requires leukemic expression of MHCI and MHCII, respectively. Thus both CD8-mediated GVHD and GVL required cognate T cell:target interactions. However, for CD4 cells only GVL, but not GVHD required target cell MHCII expression. This indicates that CD4-mediated GVL and GVHD have distinct mechanisms of action. Further understanding of these may provide insight in how to deliver GVL with less GVHD.

Chemokine-mediated tissue recruitment of CXCR3+ CD4+ T cells plays a major role in the pathogenesis of chronic GVHD

Blood ◽  
2012 ◽  
Vol 120 (20) ◽  
pp. 4246-4255 ◽  
Author(s):  
Joanne E. Croudace ◽  
Charlotte F. Inman ◽  
Ben. E. Abbotts ◽  
Sandeep Nagra ◽  
Jane Nunnick ◽  
...  
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Central Feature ◽  
Serum Concentrations ◽  
Cd4 Cells ◽  
Hemopoietic Cells ◽  
Immune Mediated

Abstract Chemokines regulate the migration of hemopoietic cells and play an important role in the pathogenesis of many immune-mediated diseases. Intradermal recruitment of CD8+ T cells by CXCL10 is a central feature of the pathogenesis of cutaneous acute GVHD (aGVHD), but very little is known about the pathogenesis of chronic GVHD (cGVHD). Serum concentrations of the 3 CXCR3-binding chemokines, CXCL9, CXCL10, and CXCL11, were found to be markedly increased in patients with active cGVHD of the skin (n = 8). An 80% decrease in CD4+ cells expressing CXCR3 was seen in the blood of these patients (n = 5), whereas CD4+ cells were increased in tissue biopsies and were clustered around the central arterioles of the dermis. The well-documented increase in expression of CXCL10 in aGVHD therefore diversifies in cGVHD to include additional members of the CXCR3-binding family and leads to preferential recruitment of CD4+ T cells. These observations reveal a central role for chemokine-mediated recruitment of CXCR3+ T cells in cGVHD.

scholarly journals Neuraminidase-treated macrophages stimulate allogenic CD8+ T cells in the presence of exogenous interleukin 2.

1988 ◽  
Vol 168 (4) ◽  
pp. 1443-1456 ◽  
Author(s):  
Y Hirayama ◽  
K Inaba ◽  
M Inaba ◽  
T Kato ◽  
M Kitaura ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
B Cells ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Class I ◽  
Cd4 Cells ◽  
Class I Mhc ◽  
Neuraminidase Treatment

Prior work has shown that purified, resident, and inflammatory peritoneal macrophages are weak stimulators of the allogeneic MLR. We have identified conditions whereby thioglycollate-elicited macrophages become stimulatory, but primarily for the CD8+ T cell subset. The conditions were to treat the macrophages with neuraminidase and to supplement the MLR with rIL-2. These treatments together led to proliferative and cytotoxic responses by isolated CD8+ but not CD4+ T cells. Likewise when MHC-congenic strains were evaluated, an MLR was observed across isolated class I but not class II MHC barriers. Pretreatment of the macrophages with IFN-gamma further enhanced expression of class I MHC products and stimulatory activity, but did not seem essential. While these treatments did not render macrophages stimulatory for an MLR in purified CD4+ cells, blastogenesis of CD4+ cells was observed when the MLR involved bulk T cells. Small allogeneic B lymphocytes behaved similarly to macrophages, in the pretreatment with neuraminidase and supplementation with rIL-2 rendered B cells stimulatory for allogeneic, enriched, CD8+, but not CD4+, T cells. Spleen adherent cells, which are mixtures of macrophages and dendritic cells, stimulated both CD4+ and CD8+ T cells, and neither neuraminidase nor exogenous IL-2 was required. We think that these data suggest that most macrophages and small B cells lack three important functions of dendritic cells: a T cell-binding function that can be remedied by neuraminidase treatment, a T cell growth factor-inducing function that can be bypassed with exogenous IL-2, and an IL-2 responsiveness function that is required by CD4+ lymphocytes.

scholarly journals Reduced immune-regulatory molecule expression on human colonic memory CD4 T cells in older adults

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Stephanie M. Dillon ◽  
Tezha A. Thompson ◽  
Allison J. Christians ◽  
Martin D. McCarter ◽  
Cara C. Wilson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Older Persons ◽  
Age Groups ◽  
T Cell Immunity ◽  
Cd4 T Cell ◽  
Cell Immunity ◽  
Memory Cd4 T Cells

Abstract Background The etiology of the low-level chronic inflammatory state associated with aging is likely multifactorial, but a number of animal and human studies have implicated a functional decline of the gastrointestinal immune system as a potential driver. Gut tissue-resident memory T cells play critical roles in mediating protective immunity and in maintaining gut homeostasis, yet few studies have investigated the effect of aging on human gut T cell immunity. To determine if aging impacted CD4 T cell immunity in the human large intestine, we utilized multi-color flow cytometry to measure colonic lamina propria (LP) CD4 T cell frequencies and immune-modulatory marker expression in younger (mean ± SEM: 38 ± 1.5 yrs) and older (77 ± 1.6 yrs) adults. To determine cellular specificity, we evaluated colon LP CD8 T cell frequency and phenotype in the same donors. To probe tissue specificity, we evaluated the same panel of markers in peripheral blood (PB) CD4 T cells in a separate cohort of similarly aged persons. Results Frequencies of colonic CD4 T cells as a fraction of total LP mononuclear cells were higher in older persons whereas absolute numbers of colonic LP CD4 T cells per gram of tissue were similar in both age groups. LP CD4 T cells from older versus younger persons exhibited reduced CTLA-4, PD-1 and Ki67 expression. Levels of Bcl-2, CD57, CD25 and percentages of activated CD38+HLA-DR+ CD4 T cells were similar in both age groups. In memory PB CD4 T cells, older age was only associated with increased CD57 expression. Significant age effects for LP CD8 T cells were only observed for CTLA-4 expression, with lower levels of expression observed on cells from older adults. Conclusions Greater age was associated with reduced expression of the co-inhibitory receptors CTLA-4 and PD-1 on LP CD4 T cells. Colonic LP CD8 T cells from older persons also displayed reduced CTLA-4 expression. These age-associated profiles were not observed in older PB memory CD4 T cells. The decline in co-inhibitory receptor expression on colonic LP T cells may contribute to local and systemic inflammation via a reduced ability to limit ongoing T cell responses to enteric microbial challenge.

scholarly journals Immune classification of clear cell renal cell carcinoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sumeyye Su ◽  
Shaya Akbarinejad ◽  
Leili Shahriyari
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Renal Cell ◽  
Cd4 T Cells ◽  
Immune Cell ◽  
Clear Cell ◽  
P Value ◽  
Cell Type ◽  
Primary Tumors ◽  
Immune Cell Type

AbstractSince the outcome of treatments, particularly immunotherapeutic interventions, depends on the tumor immune micro-environment (TIM), several experimental and computational tools such as flow cytometry, immunohistochemistry, and digital cytometry have been developed and utilized to classify TIM variations. In this project, we identify immune pattern of clear cell renal cell carcinomas (ccRCC) by estimating the percentage of each immune cell type in 526 renal tumors using the new powerful technique of digital cytometry. The results, which are in agreement with the results of a large-scale mass cytometry analysis, show that the most frequent immune cell types in ccRCC tumors are CD8+ T-cells, macrophages, and CD4+ T-cells. Saliently, unsupervised clustering of ccRCC primary tumors based on their relative number of immune cells indicates the existence of four distinct groups of ccRCC tumors. Tumors in the first group consist of approximately the same numbers of macrophages and CD8+ T-cells and and a slightly smaller number of CD4+ T cells than CD8+ T cells, while tumors in the second group have a significantly high number of macrophages compared to any other immune cell type (P-value $$<0.01$$ < 0.01 ). The third group of ccRCC tumors have a significantly higher number of CD8+ T-cells than any other immune cell type (P-value $$<0.01$$ < 0.01 ), while tumors in the group 4 have approximately the same numbers of macrophages and CD4+ T-cells and a significantly smaller number of CD8+ T-cells than CD4+ T-cells (P-value $$<0.01$$ < 0.01 ). Moreover, there is a high positive correlation between the expression levels of IFNG and PDCD1 and the percentage of CD8+ T-cells, and higher stage and grade of tumors have a substantially higher percentage of CD8+ T-cells. Furthermore, the primary tumors of patients, who are tumor free at the last time of follow up, have a significantly higher percentage of mast cells (P-value $$<0.01$$ < 0.01 ) compared to the patients with tumors for all groups of tumors except group 3.

scholarly journals Activated CD4+ CD25+ T cells suppress antigen-specific CD4+ and CD8+ T cells but induce a suppressive phenotype only in CD4+ T cells

Immunology ◽  
2005 ◽  
Vol 115 (3) ◽  
pp. 305-314 ◽  
Author(s):  
Detlef Dieckmann ◽  
Heidi Plottner ◽  
Stefanie Dotterweich ◽  
Gerold Schuler
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Suppressive Phenotype
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