Effect of chemoradiation for cervical cancer on transient decrease and variable expansion in T-cell infiltrate and diversity of T-cell repertoire.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11557-11557
Author(s):  
Lauren Elizabeth Colbert ◽  
Stephanie Dorta-Estremera ◽  
Rebecca A. Previs ◽  
Patricia J. Eifel ◽  
Anuja Jhingran ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
T Cell ◽  
Complete Response ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
Response To Treatment ◽  
Cell Repertoire ◽  
Cd8 Cells ◽  
Multiparametric Flow Cytometry ◽  
End Of Treatment

11557 Background: The effect of fractionated radiation on intratumoral immune infiltrate is unclear. The purpose of this study was to characterize local immune changes and treatment response during chemoradiation (CRT). Methods: Cervical cancer patients underwent cisplatin based CRT over 5 weeks with brachytherapy. Cervical DNA swabs and cytology brushings were collected at baseline, one week, three weeks and five weeks. Deep T cell receptor β sequencing (TCR; Adaptive, Seattle WA) and multiparametric flow cytometry (MPFC) were performed for each time point. T cell density (TCD) and productive clonality (PC) were analyzed. Cells separated from the tumor brushings were stained and fixed with antibodies to T cell subsets with activation and suppressor markers including CD3, CD4, CD8, Ki67, PD-1, CTLA-4, and ICOS. Changes in T cell subsets were evaluated as percentage of live lymphocytes. Results: Eight patients were evaluated using MPFC. CD4 and CD8 percentages were lowest at one week and subsequently expanded. The percentage of proliferating CD4 (CD4+ Ki67+) was highest at week 5 (1.19%). There was no change in percentage of CD8+ cells expressing PD1, CTLA4 or ICOS over the course of treatment. TCR diversity was assessed for 9 patients. At baseline, week 1, week 3 and week 5, median TCD for all patients were 0.046 (IQR 0.008 to 0.097), 0.021 (IQR 0.005 to 0.043), 0.035 (IQR 0.015 to 0.083), and 0.033 (IQR 0.017 to 0.110). Median productive clonality at each point was 0.05 (IQR 0.06 to 0.02), 0.03 (IQR 0.06 to 0.02), 0.04 (IQR 0.05 to 0.02) and 0.03 (IQR 0.01 to 0.05). PC fold count increased (1.69, SD 1.3) for complete response (CR) patients and decreased 0.3 (SD 0.008) for patients with recurrent (REC) disease (p = 0.1). One TCR sequence was common in 4/9 patients at the end of treatment and six sequences were common in 3/9 patients. Conclusions: Chemoradiation induces a transient decline in tumor infiltrating CD8+ and CD4+ cells, followed by a variable expansion in T-cells at the end of treatment with an increase in proliferation phenotypes. TCR sequencing revealed increase in productive clonality during radiation for patients with a complete response to treatment.

Analysis of the Human T Cell Receptor (TCR) Repertoire from Birth to Old Age Suggests That TCRVβfrequencies Are Established Independent of HLA.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3313-3313
Author(s):  
J. Joseph Melenhorst ◽  
Josette Zeilah ◽  
Edgardo Sosa ◽  
Dean Follmann ◽  
Nancy F. Hensel ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Protein Expression ◽  
Rank Order ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
Rank Test ◽  
Cell Repertoire ◽  
Cd8 Cells ◽  
Human T Cell

Abstract Human T cell development occurs in two waves of development and proliferation: first, early T cells expressing the TCRb chain but not the α-chain are selected for functional TCRβ protein independent of HLA recognition, a process called β-selection; second, thymocytes expressing both the α- and β-TCR are selected for intermediate affinity for self-MHC/ self-peptide complex. This latter process is referred to as positive selection. We sought to determine whether the peripheral TCRVβ frequencies in the naïve T cell repertoire start off at a fixed rank order with minimal skewing as would be expected from a predominantly β-selected repertoire. A total of 22 TCRVβ proteins was quantitated by flow cytometry in a group of 20 unselected umbilical cord blood (UCB) samples (a kind gift from Dr. P. Rubinstein, NY Blood Center, NY), consisting of >80% naïve T cells as defined by CD27+CD45RA+ staining in CD4+ and CD8+ cells. A common rank order of TCRVβ protein frequencies was found in both CD4 and CD8 T cell subsets (figure 1). Median TCRVβ frequencies in CD4 and in CD8 cells of UCB were statistically not significantly different from the frequencies in adult donor CD4 and CD8 cells (Wilcoxon signed rank test; p > 0.2). Furthermore, the percentages of CD4 cells expressing a particular Vβ correlated significantly in CD8 cells (figure 2) with some Vβ proteins being predominantly expressed by either CD4 (Vβ2, Vβ5.1) or CD8 (Vβ14, Vβ7) cells. Our data therefore conform to the prediction that the TCRVβ frequencies are dominantly shaped by β-selection, and not by interactions of the αβTCR/ co-receptor with MHC/ antigen complexes during thymic selection. Figure 1. TCRBV in UCB CD4+ (top) and CD8+ (bottom) T cells Figure 1. TCRBV in UCB CD4+ (top) and CD8+ (bottom) T cells Figure 2. Comparison of TCRBV protein expression frequencies in CD4 and CD8 cells of UCB Figure 2. Comparison of TCRBV protein expression frequencies in CD4 and CD8 cells of UCB

scholarly journals T suppressor cell growth factor and anti-CD3 antibodies stimulate reciprocal subsets of T lymphocytes.

1987 ◽  
Vol 166 (2) ◽  
pp. 404-418 ◽  
Author(s):  
E J Fox ◽  
D E Lewis ◽  
K P Deemer ◽  
M N ElMasry ◽  
R R Rich
Keyword(s):  
T Cell ◽  
Growth Factor ◽  
Cell Growth ◽  
Cell Surface ◽  
Suppressor Cell ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
Dependent Manner ◽  
Cell Surface Antigens ◽  
Cd8 Cells

Because of the central role of IL-2 in clonal expansion of T cells, we have postulated that lymphocyte subpopulations with opposing regulatory functions might be independently regulated by differential requirements for expression of cell-surface IL-2-R. Purified CD4+ and CD8+ cells proliferated in an IL-2-dependent manner to crosslinked anti-T cell receptor antibodies (anti-CD3-Seph). Similarly, both CD4+ and CD8+ cells became IL-2 responsive after incubation in T suppressor cell growth factor (TsGF), a newly described approximately 8,000 Mr product of activated CD4+ cells. In support of our hypothesis, however, we observed that subpopulations of CD4+ and CD8+ cells, possessing distinct cell-surface antigens, showed differential responses to these stimuli. Those cells of suppressor-inducer or suppressor-effector phenotype failed to proliferate when cultured in anti-CD3-Seph plus IL-2, but did proliferate in an IL-2-dependent manner to TsGF. Furthermore, the suppressor-effector population was unresponsive to TsGF plus IL-2 when cocultured in anti-CD3-Seph, suggesting that functionally induced Ts may be refractory to growth stimuli. Conversely, cells with helper-inducer or cytolytic phenotype proliferated when incubated in anti-CD3-Seph and IL-2, while remaining essentially unresponsive to TsGF and IL-2. The results could not be explained by differences in the level of CD3 expression by the T cell subsets. Thus, cells within the helper and suppressor lineages appear to have distinct and reciprocal patterns for the induction of IL-2 responsiveness.

scholarly journals Antigen-Driven T-Cell Selection in Patients with Cervical Cancer as Evidenced by T-Cell Receptor Analysis and Recognition of Autologous Tumor

2002 ◽  
Vol 9 (2) ◽  
pp. 267-278 ◽  
Author(s):  
H. Pilch ◽  
H. Höhn ◽  
C. Neukirch ◽  
K. Freitag ◽  
P. G. Knapstein ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
T Cell ◽  
T Cell Receptor ◽  
Tumor Tissue ◽  
Cell Receptor ◽  
Autologous Tumor ◽  
Short Term ◽  
Cell Repertoire ◽  
Tcr Repertoire ◽  
Selection Of

ABSTRACT We characterized the T-cell receptor (TCR) repertoire in freshly harvested tumor lesions, in short-term-expanded CD4+ tumor infiltrating lymphocytes (TIL) as well as in CD4+ and CD8+ peripheral blood lymphocytes (PBL) from three patients with cervical cancer. Skewing of the T-cell repertoire as defined by measuring the length of the complementarity-determining region 3 (CDR3) of the TCR VA and VB chains was observed in CD8+ PBL, in freshly harvested tumor tissue, as well as in CD4+ TIL. Comparative analysis of the TCR repertoire revealed unique monoclonal TCR transcripts within the tumor lesion which were not present in PBL, suggesting selection of TCR clonotypes due to antigenic stimulation. TCR repertoire analysis of the short-term (7-day) CD4+ TIL lines revealed that the TCR composition is markedly different from that in CD4+ PBL or in the freshly harvested tumor tissue. Only one-third of CD4+ TIL lines showed HLA-DR-restricted recognition of autologous tumor cells as defined by cytolysis. These data provide support for the antigen-driven selection of T cells within cervical cancer lesions and suggest that analysis of the TCR repertoire may aid in obtaining an objective description of the immune response in patients with cervical cancer who are undergoing epitope-based immunotherapy.

scholarly journals Development of a CD8 co-receptor independent T-cell receptor specific for tumor-associated antigen MAGE-A4 for next generation T-cell-based immunotherapy

2021 ◽  
Vol 9 (3) ◽  
pp. e002035
Author(s):  
Kathrin Davari ◽  
Tristan Holland ◽  
Laura Prassmayer ◽  
Giulia Longinotti ◽  
Kenneth P Ganley ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
In Vivo Studies ◽  
High Avidity ◽  
Cell Repertoire

BackgroundThe cancer-testis antigen MAGE-A4 is an attractive target for T-cell-based immunotherapy, especially for indications with unmet clinical need like non-small cell lung or triple-negative breast cancer.MethodsAn unbiased CD137-based sorting approach was first used to identify an immunogenic MAGE-A4-derived epitope (GVYDGREHTV) that was properly processed and presented on human leukocyte antigen (HLA)-A2 molecules encoded by the HLA-A*02:01 allele. To isolate high-avidity T cells via subsequent multimer sorting, an in vitro priming approach using HLA-A2-negative donors was conducted to bypass central tolerance to this self-antigen. Pre-clinical parameters of safety and activity were assessed in a comprehensive set of in vitro and in vivo studies.ResultsA MAGE-A4-reactive, HLA-A2-restricted T-cell receptor (TCR) was isolated from primed T cells of an HLA-A2-negative donor. The respective TCR-T-cell (TCR-T) product bbT485 was demonstrated pre-clinically to have a favorable safety profile and superior in vivo potency compared with TCR-Ts expressing a TCR derived from a tolerized T-cell repertoire to self-antigens. This natural high-avidity TCR was found to be CD8 co-receptor independent, allowing effector functions to be elicited in transgenic CD4+ T helper cells. These CD4+ TCR-Ts supported an anti-tumor response by direct killing of MAGE-A4-positive tumor cells and upregulated hallmarks associated with helper function, such as CD154 expression and release of key cytokines on tumor-specific stimulation.ConclusionThe extensive pre-clinical assessment of safety and in vivo potency of bbT485 provide the basis for its use in TCR-T immunotherapy studies. The ability of this non-mutated high-avidity, co-receptor-independent TCR to activate CD8+ and CD4+ T cells could potentially provide enhanced cellular responses in the clinical setting through the induction of functionally diverse T-cell subsets that goes beyond what is currently tested in the clinic.

The Croonian Lecture, 1992. The key role of the thymus in the body’s defence strategies

1992 ◽  
Vol 337 (1279) ◽  
pp. 105-124 ◽  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Bone Marrow Cells ◽  
Cell Receptor ◽  
Division Of Labour ◽  
T Cell Subsets ◽  
Lymphoid Tissues ◽  
Cell Repertoire ◽  
Long Time ◽  
T Cell Selection

For centuries the thymus has remained a mysterious organ with largely unknown functions. The first demonstration of its crucial role in the development of the immune system was reported in 1961, when it was found that mice thymectomized at birth had poorly developed lymphoid tissues, impaired immune reactivities, and an inordinate susceptibility to develop infections. Although thymus lymphocytes were for a long time deemed immunoincompetent, it was shown in 1967 that they could respond to antigen by proliferating to give rise to a progeny of cells which did not secrete antibody (T cells), but which had a remarkable ability to induce bone marrow cells (B cells) to become antibody formers. This was the first unequivocal demonstration of a major division of labour among mammalian lymphocytes. Tremendous progress in our understanding of the function of the thymus and of the T cells derived from it followed. Distinct T cell subsets were characterized and shown to have an essential role in initiating and regulating a variety of immune responses. The ontogenetic events which occurred during their differentiation were mapped, and this allowed studies of the selection of the T cell repertoire. The major histocompatibility complex and associated peptides were shown to govern T cell selection and antigen activation, and the antigen-specific T cell receptor and the genes which code for it were characterized. Future studies should allow some insight into how to activate T cells more effectively for vaccination purposes, and how to switch them off to prevent autoimmune reactions and to induce tolerance to transplanted tissues.

Functional and Numerical T Cell Abnormalities in Chronic Lymphocytic Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3085-3085
Author(s):  
Mark C. Lanasa ◽  
Marc C. Levesque ◽  
Sallie D. Allgood ◽  
Jon P. Gockerman ◽  
Karen Bond ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
T Cell Repertoire ◽  
Cell Repertoire ◽  
Unequal Variances

Abstract Background: Although most malignancies are associated with decreased numbers of circulating T cells, in CLL they are elevated 2 to 4 times normal. Rather than promoting an anti-tumor response, this increased population of T cells may contribute to a tumor microenvironment that fosters progression of the malignant clone. Immunocompetent individuals show a wide repertoire of antigen specificity in both CD4+ and CD8+ T cells, but the T cell repertoire is significantly restricted in CLL. This restriction of the T cell repertoire may be an important cause of infectious morbidity in patients with CLL. To better understand these T cell abnormalities, we enumerated T cell subsets and determined T cell receptor diversity in 18 untreated patients with CLL. Methods: T cell subsets were enumerated from peripheral blood using highly sensitive 6-color flow cytometry. The T cell repertoire was determined for 23 T cell receptor variable β chain families (TCRvβ) in purified CD4+ and CD8+ T cells. These T cell subsets were considered separately because differential restriction of the CD4+ and CD8+ subsets has been reported previously. A PCR-based spectratype assay was used to analyze the length distribution of the TCR complementarity-determining region 3 (CDR3). A limitation of prior reports using spectratype assays was that adequately complex statistical models did not exist to simultaneously analyze the highly diverse vβ families. We addressed this limitation by using a recently-developed statistical method for spectratype analysis (Bioinformatics. 21:3394–400). Briefly, for each vβ family, the divergence from an expected reference distribution was calculated. A divergence coefficient was determined for each vβ family, and the mean divergence of all 23 vβ families was calculated. This allowed for statistical comparisons among individual patients and specific vβ families. To our knowledge, we are the first group to apply this powerful methodology to the analysis of T cell repertoires in patients with CLL. Results: We found both the CD4+ and CD8+ subsets to be expanded (mean #/μL ± SD: 1134 ± 646 and 768 ± 716, respectively; reference normal CD4+ range 401–1532, CD8+ 152–838). The absolute number of CD4+ and CD8+ T cells was greater in patients with higher absolute CLL lymphocyte counts (p = 0.018, r2 = 0.30, and p = 0.23, r2 = 0.09, respectively, linear regression). The CD4:CD8 ratio was lower in IgVH unmutated subjects (mutated 2.6, umutated 1.7, p = 0.09, two-tailed t-test assuming unequal variances). Though prior reports have disagreed on whether CD4+ or CD8+ subsets show greater restriction of clonality, we observed striking clonal restriction of CD8+ but not CD4+ T cells (p < 1×10−7, 2 sided t-test assuming unequal variances). There was a trend toward greater restriction of the CD8+ subset among patients with IgVH unmutated and Zap70+ CLL, but there was no correlation with lymphocyte doubling time. Conclusions: In this cohort of 18 untreated patients with CLL, there was a greater proportional increase compared to reference standards of CD8+ versus CD4+ T cells. However, the increase in CD4+, but not CD8+, T cell numbers was significantly correlated to total CLL lymphocyte count. This observation suggests that expansion of the CD4+ T cell pool observed in CLL is proportional to leukemic burden. The restriction of TCRvβ was limited to CD8+ T cells and that this effect was independent of the size of the abnormal clone. Taken together, these findings suggest different mechanisms of dysregulation of CD4+ and CD8+ T cell subsets in CLL.

scholarly journals Acquired Mls-1a-like clonal deletion in Mls-1b mice.

1992 ◽  
Vol 175 (2) ◽  
pp. 453-460 ◽  
Author(s):  
M Papiernik ◽  
C Pontoux ◽  
S Gisselbrecht
Keyword(s):  
T Cells ◽  
T Cell ◽  
Bone Marrow Cells ◽  
Cell Receptor ◽  
Cell Repertoire ◽  
Clonal Deletion ◽  
Genetic Transmission ◽  
Cd8 Cells ◽  
High Level

BALB/c mice (H-2d, Mls-1b) from one colony progressively modify their T cell repertoire during aging, by deleting T cells that express products of the V beta 6 and V beta 8.1 genes of the T cell receptor. Clonal deletion occurs only in 50% of mice between 27 and 43 wk of age, affecting thymus, spleen, and lymph node T cells. The phenomenon is progressive and seems to affect nearly all thymuses between 14 and 19 wk of age. CD4+CD8- mature T cells are more affected than CD4-CD8+ cells. In the thymus, deletion occurs at the stage of immature J11d+ cells expressing a high level of V beta 6, while J11d+V beta 6low-expressing cells are not modified. Clonal deletion is thus an early phenomenon that deletes cells of the immature generative compartment in the thymus. This Mls-1a-like clonal deletion is associated neither with the expression of an Mls-1a-like antigen that could be identified in mixed lymphocyte reaction in vitro, nor with the presence of Mtv-7, the endogenous mouse mammary tumor virus (MMTV) proviral loci. Spleen cells, bone marrow cells, and total thymocytes injected into newborn thymuses cannot induce V beta 6+ cell deletion. However, newborn thymuses grafted into old BALB/c mice behave like their recipients, suggesting that a new antigen, present in these old BALB/c mice, is indeed able to induce an Mls-1a-like clonal deletion. As other BALB/c colonies tested do not behave in same way, the hypothesis of a new exogenous deleting factor rather than a genetic transmission is likely. This may suggest that acquired clonal deletion is a more common phenomenon than expected, and may be the spontaneous reaction of the immune system to the introduction of a new retrovirus or other superantigen.

scholarly journals Treatment With Cladribine Selects IFNγ+IL17+ T Cells in RRMS Patients – An In Vitro Study

2021 ◽  
Vol 12 ◽  
Author(s):  
Minodora Dobreanu ◽  
Doina Ramona Manu ◽  
Ion Bogdan Mănescu ◽  
Manuela Rozalia Gabor ◽  
Adina Huţanu ◽  
...  
Keyword(s):  
T Cell ◽  
Experimental Model ◽  
Culture Media ◽  
Ex Vivo ◽  
Interleukin 2 ◽  
In Vitro Study ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
Multiparametric Flow Cytometry

BackgroundMultiple sclerosis (MS) is an incurable autoimmune disease mediated by a heterogeneous T cell population (CD3+CD161+CXCR3−CCR6+IFNγ−IL17+, CD3+CXCR3+CCR6+IFNγ+IL17+, and CD3+CXCR3+IFNγ+IL17− phenotypes) that infiltrates the central nervous system, eliciting local inflammation, demyelination and neurodegeneration. Cladribine is a lymphocyte-depleting deoxyadenosine analogue recently introduced for MS therapy as a Disease Modifying Drug (DMD). Our aim was to establish a method for the early identification and prediction of cladribine responsiveness among MS patients.MethodsAn experimental model was designed to study the cytotoxic and immunomodulatory effect of cladribine. T cell subsets of naïve relapsing-remitting MS (RRMS) patients were analyzed ex vivo and in vitro comparatively to healthy controls (HC). Surviving cells were stimulated with rh-interleukin-2 for up to 14days. Cell proliferation and immunophenotype changes were analyzed after maximal (phorbol myristate acetate/ionomycin/monensin) and physiological T-cell receptor (CD3/CD28) activation, using multiparametric flow cytometry and xMAP technology.ResultsEx vivo CD161+Th17 cells were increased in RRMS patients. Ex vivo to in vitro phenotype shifts included: decreased CD3+CCR6+ and CD3+CD161+ in all subjects and increased CD3+CXCR3+ in RRMS patients only; Th17.1 showed increased proliferation vs Th17 in all subjects; CD3+IL17+ and CD3+IFNγ+IL17+ continued to proliferate till day 14, CD3+IFNγ+ only till day 7. Regarding cladribine exposure: RRMS CD3+ cells were more resistant compared to HC; treated CD3+ cells proliferated continuously for up to 14 days, while untreated cells only up to 7 days; both HC/RRMS CD3+CXCR3+ populations increased from baseline till day 14; in RRMS patients vs HC, IL17 secretion from cladribine-treated cells increased significantly, in line with the observed proliferation of CD3+IL17+ and CD3+IFNγ+IL17+ cells; in both HC/RRMS, cladribine led to a significant increase in CD3+IFNγ+ cells at day 7 only, having no further effect at day14. IFNγ and IL17 secreted in culture media decreased significantly from ex vivo to in vitro.ConclusionsCD3+ subtypes showed different responsiveness due to selectivity of cladribine action, in most patients leading to in vitro survival/proliferation of lymphocyte subsets known as pathogenic in MS. This in vitro experimental model is a promising tool for the prediction of individual responsiveness of MS patients to cladribine and other DMDs.

scholarly journals Comprehensive analysis of structural and sequencing data reveals almost unconstrained chain pairing in TCRαβ complex

2019 ◽  
Author(s):  
Dmitrii S Shcherbinin ◽  
Vlad A Belousov ◽  
Mikhail Shugay
Keyword(s):  
T Cells ◽  
T Cell ◽  
Structural Data ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
Sequencing Data ◽  
Antigen Specificity ◽  
Cell Repertoire ◽  
Effective Response ◽  
Specific Choice

AbstractAntigen recognition by T-cells is guided by the T-cell receptor (TCR) heterodimer formed by α and β chains. A huge diversity of TCR sequences should be maintained by the immune system in order to be able to mount an effective response towards foreign pathogens, so, due to cooperative binding of α and β chains to the pathogen, any constraints on chain pairing can have a profound effect on immune repertoire structure, diversity and antigen specificity. By integrating available structural data and paired chain sequencing results we were able to show that there are almost no constraints on pairing in TCRαβ complexes, allowing naive T-cell repertoire to reach the highest possible diversity. Additional analysis reveals that the specific choice of contacting amino acids can still have a profound effect on complex conformation. Moreover, antigen-driven selection can distort the uniform landscape of chain pairing, while small, yet significant, differences in the pairing can be attributed to various specialized T-cell subsets such as MAIT and iNKT T-cells, as well as other putative invariant TCRs.

scholarly journals Oligoclonal CD4+CD57+ T-Cell Expansions Contribute to the Imbalanced T-Cell Receptor Repertoire of Rheumatoid Arthritis Patients

Blood ◽  
1997 ◽  
Vol 89 (8) ◽  
pp. 2822-2832 ◽  
Author(s):  
Luisa Imberti ◽  
Alessandra Sottini ◽  
Simona Signorini ◽  
Roberto Gorla ◽  
Daniele Primi
Keyword(s):  
Rheumatoid Arthritis ◽  
T Cell ◽  
T Cell Receptor ◽  
Peripheral Blood ◽  
Cell Receptor ◽  
Small Subset ◽  
Cell Repertoire ◽  
Cd8 Cells ◽  
Receptor Repertoire ◽  
Cd4 Cell

Abstract A peculiar feature of rheumatoid arthritis patients is that they carry clonally expanded CD4+ and CD8+ cells in the peripheral blood. While the distortion of the repertoire of CD8+ cells has been ascribed to the increase of CD8+CD57+ large granular lymphocytes, often detected in these patients, the mechanism responsible for the clonal expansion of CD4+ cells remains unexplained. Here, we report that CD4+CD57+ cells, that in healthy individuals represent a small subset of peripheral CD4+ lymphocytes, are significantly expanded in the peripheral blood of a considerable percentage of rheumatoid arthritis patients. Furthermore, the expansion of these lymphocytes appears to correlate with the presence of rheumatoid factor. The molecular analysis of the T-cell receptor variable beta segments expressed by the CD4+CD57+ cells enriched in rheumatoid arthritis patients showed that they use restricted repertoires, that partially overlap with those of their CD4−CD57+ counterpart. The structural feature of the receptor ligand expressed by these cells revealed that their expansion is most likely mediated by strong antigenic pressures. However, since we also found that CD4+CD57+ and CD4−CD57+ cells can share the same clonal specificity, it is likely that their selection is not mediated by conventional major histocompatibility complex restricted mechanisms. Thus, while our data demonstrate that CD4+CD57+ cells play an important role in establishing the imbalance of the CD4+ cell repertoire observed in rheumatoid arthritis patients, they also suggest that these cells have common features with mouse CD4+CD8−NK1.1+/T cells.

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