scholarly journals Vaccination establishes clonal relatives of germinal center T cells in the blood of humans

2017 ◽  
Vol 214 (7) ◽  
pp. 2139-2152 ◽  
Author(s):  
Antje Heit ◽  
Frank Schmitz ◽  
Sarah Gerdts ◽  
Britta Flach ◽  
Miranda S. Moore ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Germinal Center ◽  
Cell Subset ◽  
Cell Receptor ◽  
B Cell Differentiation ◽  
Booster Immunization ◽  
Receptor Repertoire ◽  
Follicular Helper ◽  
Antibody Induction

Germinal center T follicular helper cells (GCTfh) in lymphatic tissue are critical for B cell differentiation and protective antibody induction, but whether GCTfh establish clonal derivatives as circulating memory T cells is less understood. Here, we used markers expressed on GCTfh, CXCR5, PD1, and ICOS, to identify potential circulating CXCR5+CD4+ Tfh-like cells (cTfh) in humans, and investigated their functional phenotypes, diversity, and ontogeny in paired donor blood and tonsils, and in blood after vaccination. Based on T cell receptor repertoire analysis, we found that PD-1–expressing cTfh and tonsillar GCTfh cells were clonally related. Furthermore, an activated, antigen-specific PD1+ICOS+ cTfh subset clonally expanded after booster immunization whose frequencies correlated with vaccine-specific serum IgG; these phenotypically resembled GCTfh, and were clonally related to a resting PD1+ICOS− CD4+ memory T cell subset. Thus, we postulate that vaccination establishes clonal relatives of GCTfh within the circulating memory CD4+CXCR5+PD1+ T cell pool that expand upon reencounter of their cognate antigen.

scholarly journals Naïve Regulatory T Cell Subset Is Altered in X-Linked Agammaglobulinemia

2021 ◽  
Vol 12 ◽  
Author(s):  
Pavel V. Shelyakin ◽  
Ksenia R. Lupyr ◽  
Evgeny S. Egorov ◽  
Ilya A. Kofiadi ◽  
Dmitriy B. Staroverov ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cell Subset ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
Cell Compartments ◽  
Expression Of Genes ◽  
Tcr Repertoire ◽  
Antigen Presenting

The interplay between T- and B-cell compartments during naïve, effector and memory T cell maturation is critical for a balanced immune response. Primary B-cell immunodeficiency arising from X-linked agammaglobulinemia (XLA) offers a model to explore B cell impact on T cell subsets, starting from the thymic selection. Here we investigated characteristics of naïve and effector T cell subsets in XLA patients, revealing prominent alterations in the corresponding T-cell receptor (TCR) repertoires. We observed immunosenescence in terms of decreased diversity of naïve CD4+ and CD8+ TCR repertoires in XLA donors. The most substantial alterations were found within naïve CD4+ subsets, and we have investigated these in greater detail. In particular, increased clonality and convergence, along with shorter CDR3 regions, suggested narrower focused antigen-specific maturation of thymus-derived naïve Treg (CD4+CD45RA+CD27+CD25+) in the absence of B cells - normally presenting diverse self and commensal antigens. The naïve Treg proportion among naïve CD4 T cells was decreased in XLA patients, supporting the concept of impaired thymic naïve Treg selection. Furthermore, the naïve Treg subset showed prominent differences at the transcriptome level, including increased expression of genes specific for antigen-presenting and myeloid cells. Altogether, our findings suggest active B cell involvement in CD4 T cell subsets maturation, including B cell-dependent expansion of the naïve Treg TCR repertoire that enables better control of self-reactive T cells.

T cell-intrinsic Interferon Regulatory Factor-1 expression suppresses differentiation of CD4 + T cell populations that support chronic gammaherpesvirus infection.

2021 ◽  
Author(s):  
C. N. Jondle ◽  
K. E. Johnson ◽  
W. P. Mboko ◽  
V. L. Tarakanova
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
T Cell Subsets ◽  
Viral Reservoir ◽  
B Cell Differentiation ◽  
Follicular Helper ◽  
Interferon Regulatory Factor 1 ◽  
Latent Viral Reservoir

Gammaherpesviruses are ubiquitous pathogens that establish life-long infection and are associated with B cell lymphomas. To establish chronic infection, these viruses usurp B cell differentiation and drive a robust germinal center response to expand the latent viral reservoir and gain access to memory B cells. Germinal center B cells, while important for the establishment of latent infection, are also thought to be the target of viral transformation. The host and viral factors that impact the gammaherpesvirus-driven germinal center response are not clearly defined. We showed that global expression of the antiviral and tumor-suppressor interferon regulatory factor 1 (IRF-1) selectively attenuates the murine gammaherpesvirus 68 (MHV68)-driven germinal center response and restricts expansion of the latent viral reservoir. In this study we found that T cell intrinsic IRF-1 expression recapitulates some aspects of antiviral state imposed by IRF-1 during chronic MHV68 infection, including attenuation of the germinal center response and viral latency in the spleen. We also discovered that global and T cell-intrinsic IRF-1 deficiency leads to unhindered rise of IL-17A-expressing and follicular helper T cell populations, two CD4 + T cell subsets that support chronic MHV68 infection. Thus, this study unveils a novel aspect of antiviral activity of IRF-1 by demonstrating IRF-1-mediated suppression of specific CD4 + T cell subsets that support chronic gammaherpesvirus infection. Importance Gammaherpesviruses infect over 95% of the adult population, last the lifetime of the host, and are associated with multiple cancers. These viruses usurp the germinal center response to establish lifelong infection in memory B cells. This manipulation of B cell differentiation by the virus is thought to contribute to lymphomagenesis, though exactly how the virus precipitates malignant transformation in vivo is unclear. IRF-1, a host transcription factor and a known tumor suppressor, restricts the MHV68-driven germinal center response in a B cell-extrinsic manner. We found that T cell intrinsic IRF-1 expression attenuates the MHV68-driven germinal center response by restricting the CD4 + T follicular helper population. Further, our study identified IRF-1 as a novel negative regulator of IL-17-driven immune responses, highlighting the multifaceted role of IRF-1 in gammaherpesvirus infection.

scholarly journals P083 Characterisation of T-cell receptor repertoire patterns of circulating a4b7 positive memory T cells in ulcerative colitis

2020 ◽  
Vol 14 (Supplement_1) ◽  
pp. S176-S177
Author(s):  
A Gamliel ◽  
L Werner ◽  
N Salamon ◽  
M Pinsker ◽  
B Weiss ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Memory T Cells ◽  
Cell Receptor ◽  
Control Subjects ◽  
Receptor Repertoire ◽  
Negative Memory ◽  
T Cell Receptor Repertoire ◽  
Cell Receptor Repertoire

Abstract Background Memory T cells play an important role in mediating inflammatory responses in IBD. The integrin a4b7 is highly expressed on activated T cells, and is thought to direct homing of lymphocytes to the intestine, following its binding to MADCAM-1 expressed exclusively on intestinal endothelial cells. Since UC is characterised by oligoclonal expansion of specific T-cell clonotypes, we hypothesised that circulating memory T cells with gut-homing potential would exhibit unique T-cell receptor repertoire features. Methods Peripheral blood mononuclear cells were collected from 5 control subjects and 6 pediatric patients with active UC. Following CD3 MACS sorting cells were FACS sorted into a4b7 positive and a4b7 negative CD3+CD45RO+ memory T cells. DNA was Isolated from each subset and subjected to next-generation sequencing of the TCRB. This high-throughput platform employs massive parallel sequencing to process millions of rearranged T-cell receptor (TCR) products simultaneously, and permits an in-depth analysis of individual TCRs at the nucleotide level. Comparisons of different indices of diversity, CDR3 length and clonal biochemical characteristics were performed between a4b7 positive and a4b7 negative populations for each subject, and between controls and UC patients. Results PBMCs were isolated from active UC patients during endoscopic assessment. Four patients had a Mayo endoscopic score of 2, and two patients had a score of 1. Only one patient was treated with an immunosuppressive medication (azathioprine), and five out of six patients were treated with 5ASAs. Percentages of memory T cells (43.8 ± 12.3% vs. 32.2 ± 13.1%, p = 0.17) and a4b7 positive T cells (33.6 ± 15.7% vs. 36.0 ± 17.6%, p = 0.81) were comparable between controls and UC patients. Interestingly, a4b7 positive memory T cells displayed a polyclonal distribution, in both control subjects and in UC patients, without expansion of specific clones. Different indices of diversity, including shanon’s H, clonality index and entropy, were similar among controls and patients, both for a4b7 positive and a4b7 negative populations. Finally, clonal overlap between a4b7 positive and a4b7 negative memory T cells, for each subject was high, ranging between 30–50% for controls and 27–48% for UC patients. Conclusion a4b7 expressing memory T cells exhibited a polyclonal repertoire in both control subjects and patients with active UC, with high rates of overlap with a4b7 negative memory T cells. Our study, along with additional recent reports, challenge the dogma of the importance of a4b7 expression for T-cell migration to the gut, and may suggest that vedolizumab’s suppresses intestinal inflammation by blocking the trafficking of innate immune subsets.

scholarly journals An invariant V alpha 24-J alpha Q/V beta 11 T cell receptor is expressed in all individuals by clonally expanded CD4-8- T cells.

1994 ◽  
Vol 180 (3) ◽  
pp. 1171-1176 ◽  
Author(s):  
P Dellabona ◽  
E Padovan ◽  
G Casorati ◽  
M Brockhaus ◽  
A Lanzavecchia
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Clone ◽  
Cell Subset ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
T Cell Clone ◽  
Gene Usage ◽  
Beta Gene

The T cell receptor (TCR)-alpha/beta CD4-8- (double negative, DN) T cell subset is characterized by an oligoclonal repertoire and a restricted V gene usage. By immunizing mice with a DN T cell clone we generated two monoclonal antibodies (mAbs) against V alpha 24 and V beta 11, which have been reported to be preferentially expressed in DN T cells. Using these antibodies, we could investigate the expression and pairing of these V alpha and V beta gene products among different T cell subsets. V alpha 24 is rarely expressed among CD4+ and especially CD8+ T cells. In these cases it is rearranged to different J alpha segments, carries N nucleotides, and pairs with different V beta. Remarkably, V alpha 24 is frequently expressed among DN T cells and is always present as an invariant rearrangement with J alpha Q, without N region diversity. This invariant V alpha 24 chain is always paired to V beta 11. This unique V alpha 24-J alpha Q/V beta 11 TCR was found in expanded DN clones from all the individuals tested. These findings suggest that the frequent occurrence of cells carrying this invariant TCR is due to peripheral expansion of rare clones after recognition of a nonpolymorphic ligand.

scholarly journals In situ quantitation of lymph node helper, suppressor, and cytotoxic T cell subsets in AIDS

Blood ◽  
1986 ◽  
Vol 67 (3) ◽  
pp. 596-603 ◽  
Author(s):  
GS Wood ◽  
BF Burns ◽  
RF Dorfman ◽  
RA Warnke
Keyword(s):  
T Cell ◽  
Lymph Nodes ◽  
Germinal Center ◽  
Feedback Inhibition ◽  
Cell Subset ◽  
Suppressor Cells ◽  
T Cell Subsets ◽  
Cytotoxic T Cell ◽  
B Cell Differentiation ◽  
T Cell Subset

Abstract We have used the novel monoclonal antibodies 9.3 and anti-Leu-8 in conjunction with other T cell markers to quantify T cell subpopulations in the paracortex, mantle, and germinal center compartments of frozen sections of lymph nodes from seven homosexual men with acquired immunodeficiency syndrome (AIDS) and five heterosexual controls. Antibody 9.3 allows dissection of the Leu-2+ cytotoxic/suppressor subset (Tcs) into 9.3+ cytotoxic cells (Tc) and 9.3- suppressor cells (Ts). Anti-Leu-8 allows dissection of the Leu-3+ helper subset (TH) into functionally distinct subpopulations. The data indicate that the T cells in patients with AIDS exhibit normal antigen expression but altered subset ratios. In this series, the data suggested that the reversal of the paracortical TH-Tcs ratio was due to an increase in Ts with a concomitant decrease in TH and Tc. These changes were also reflected in a reversal of the normal paracortical Tc-Ts ratio (3.0) to less than 1.0. Furthermore, the data suggested a marked decrease in paracortical Leu-3+8+TH, which are known to have inducer function in cellular immune reactions and exert feedback inhibition of immunoglobulin production through a suppressor T cell intermediary. In contrast, there was preservation of the Leu-3+8-TH population within the germinal center. This T cell subset is known to help B cell differentiation. This microenvironmentally specific constellation of T cell subset alterations within lymph nodes may in part explain several of the immunologic findings associated with AIDS.

scholarly journals PPARγ Negatively Regulates T Cell Activation to Prevent Follicular Helper T Cells and Germinal Center Formation

PLoS ONE ◽  
2014 ◽  
Vol 9 (6) ◽  
pp. e99127 ◽  
Author(s):  
Hong-Jai Park ◽  
Do-Hyun Kim ◽  
Jin-Young Choi ◽  
Won-Ju Kim ◽  
Ji Yun Kim ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Germinal Center ◽  
Cell Activation ◽  
Helper T Cells ◽  
Follicular Helper T Cells ◽  
Follicular Helper ◽  
Germinal Center Formation

scholarly journals Distinct populations of dendritic cells are present in the subepithelial dome and T cell regions of the murine Peyer's patch.

1996 ◽  
Vol 183 (1) ◽  
pp. 237-247 ◽  
Author(s):  
B L Kelsall ◽  
W Strober
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd8 T Cells ◽  
Germinal Center ◽  
Cell Receptor ◽  
Dense Layer ◽  
Peyer’S Patch ◽  
Peyer's Patch ◽  
Antigen Uptake

Despite the fact that the Peyer's patch (PP) is the primary site for antigen uptake in the intestine, the cellular basis of antigen handling after transport into the PP is poorly understood. We performed immunohistology of murine PPs using the dendritic cell (DC)-reactive monoclonal antibodies N418, NLDC-145, M342, and 2A1, as well as antibodies to other T cell, B cell, and macrophage markers. N418+, 2A1+, NLDC-145-, M342- cells form a dense layer of cells in the subepithelial dome (SED), just beneath the follicle epithelium, and are scattered throughout the follicle, sparing the germinal center. In contrast, N418+, 2A1+, NLDC-145+, and M342+ DCs are present in the interfollicular T cell regions (IFR). CD3+ and CD4+, but no CD8+ T cells were present in the SED and the follicle, including the germinal center, while CD3+, CD4+, and CD8+ T cells were present in the IFR. B cells and macrophages were poorly represented in the SED as no B220+ cells, only few Mac-1lo cells, and no F4/80+ cells were present at this site. In contrast, Mac-1hi cells were found in the IFR and lamina propria of intestinal villi, while F4/80+ cells were found only in the latter. In further phenotypic studies, we analyzed surface molecules of PP and spleen DCs by flow cytometry and found that these cells had similar fluorescence profiles when stained with N418, NLDC-145, and 33D1 DC-reactive antibodies, and antibodies to the costimulatory molecules B7-1 (1G10) and B7-2 (GL1). In contrast, PP DCs expressed 5-10-fold higher levels of major histocompatibility complex class II antigens (IEk) than spleen DCs. Finally, in functional studies, we demonstrated that both PP and spleen DCs process soluble protein antigens during overnight culture and induce similar levels of proliferation in CD3+ T cells, and CD4+/Mel 14hi T cells from T cell receptor transgenic mice. The in vivo relevance of such presentation was shown by the fact that PP DCs isolated from Balb/c mice after being fed ovalbumin stimulated proliferation in ovalbumin T cell receptor T cells. Taken together, our data suggest that DCs in the SED of the PP are uniquely positioned for the processing of antigens passed into the PP from the overlying M cell, and that PP DCs are effective at processing and presenting oral antigens to naive T cells.

T-cell receptor repertoire of circulating gamma delta T-cells in Takayasu's arteritis

2006 ◽  
Vol 118 (2-3) ◽  
pp. 243-249 ◽  
Author(s):  
Sunil Kumar Chauhan ◽  
Naresh Kumar Tripathy ◽  
Nakul Sinha ◽  
Soniya Nityanand
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Takayasu’S Arteritis ◽  
Cell Receptor ◽  
Gamma Delta T Cells ◽  
Gamma Delta ◽  
Receptor Repertoire ◽  
T Cell Receptor Repertoire ◽  
Cell Receptor Repertoire
Sign in / Sign up

Export Citation Format

Share Document