scholarly journals Self-recognition drives the preferential accumulation of promiscuous CD4+ T-cells in aged mice

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Neha R Deshpande ◽  
Heather L Parrish ◽  
Michael S Kuhns
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cell Biology ◽  
Fold Increase ◽  
Cell Receptor ◽  
Cd4 T Cell ◽  
Fundamental Aspect ◽  
Cell Compartment ◽  
Old Mice

T-cell recognition of self and foreign peptide antigens presented in major histocompatibility complex molecules (pMHC) is essential for life-long immunity. How the ability of the CD4+ T-cell compartment to bind self- and foreign-pMHC changes over the lifespan remains a fundamental aspect of T-cell biology that is largely unexplored. We report that, while old mice (18–22 months) contain fewer CD4+ T-cells compared with adults (8–12 weeks), those that remain have a higher intrinsic affinity for self-pMHC, as measured by CD5 expression. Old mice also have more cells that bind individual or multiple distinct foreign-pMHCs, and the fold increase in pMHC-binding populations is directly related to their CD5 levels. These data demonstrate that the CD4+ T-cell compartment preferentially accumulates promiscuous constituents with age as a consequence of higher affinity T-cell receptor interactions with self-pMHC.

CD4+ T cells specific for glycoprotein B from cytomegalovirus exhibit extreme conservation of T-cell receptor usage between different individuals

Blood ◽  
2008 ◽  
Vol 111 (4) ◽  
pp. 2053-2061 ◽  
Author(s):  
Laura Crompton ◽  
Naeem Khan ◽  
Rajiv Khanna ◽  
Laxman Nayak ◽  
Paul A. H. Moss
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Response ◽  
Cd4 T Cells ◽  
Clonal Selection ◽  
Cell Receptor ◽  
T Cell Response ◽  
Cd4 T Cell ◽  
Extreme Conservation

Antigen-specific CD8+ cytotoxic T cells often demonstrate extreme conservation of T-cell receptor (TCR) usage between different individuals, but similar characteristics have not been documented for CD4+ T cells. CD4+ T cells predominantly have a helper immune role, but a cytotoxic CD4+ T-cell subset has been characterized, and we have studied the cytotoxic CD4+ T-cell response to a peptide from human cytomegalovirus glycoprotein B presented through HLA-DRB*0701. We show that this peptide elicits a cytotoxic CD4+ T-cell response that averages 3.6% of the total CD4+ T-cell repertoire of cytomegalovirus-seropositive donors. Moreover, CD4+ cytotoxic T-cell clones isolated from different individuals exhibit extensive conservation of TCR usage, which indicates strong T-cell clonal selection for peptide recognition. Remarkably, this TCR sequence was recently reported in more than 50% of cases of CD4+ T-cell large granular lymphocytosis. Immunodominance of cytotoxic CD4+ T cells thus parallels that of CD8+ subsets and suggests that cytotoxic effector function is critical to the development of T-cell clonal selection, possibly from immune competition secondary to lysis of antigen-presenting cells. In addition, these TCR sequences are highly homologous to those observed in HLA-DR7+ patients with CD4+ T-cell large granular lymphocytosis and implicate cytomegalovirus as a likely antigenic stimulus for this disorder.

scholarly journals IL-21 from high-affinity CD4 T cells drives differentiation of brain-resident CD8 T cells during persistent viral infection

2020 ◽  
Vol 5 (51) ◽  
pp. eabb5590 ◽  
Author(s):  
Heather M. Ren ◽  
Elizabeth M. Kolawole ◽  
Mingqiang Ren ◽  
Ge Jin ◽  
Colleen S. Netherby-Winslow ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Infection ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Central Nervous System Infection ◽  
Cell Receptor ◽  
Cd4 T Cell ◽  
Persistent Viral Infection ◽  
High Affinity

Development of tissue-resident memory (TRM) CD8 T cells depends on CD4 T cells. In polyomavirus central nervous system infection, brain CXCR5hi PD-1hi CD4 T cells produce interleukin-21 (IL-21), and CD8 T cells lacking IL-21 receptors (IL21R−/−) fail to become bTRM. IL-21+ CD4 T cells exhibit elevated T cell receptor (TCR) affinity and higher TCR density. IL21R−/− brain CD8 T cells do not express CD103, depend on vascular CD8 T cells for maintenance, are antigen recall defective, and lack TRM core signature genes. CD4 T cell–deficient and IL21R−/− brain CD8 T cells show similar deficiencies in expression of genes for oxidative metabolism, and intrathecal delivery of IL-21 to CD4 T cell–depleted mice restores expression of electron transport genes in CD8 T cells to wild-type levels. Thus, high-affinity CXCR5hi PD-1hi CD4 T cells in the brain produce IL-21, which drives CD8 bTRM differentiation in response to a persistent viral infection.

scholarly journals Direct Expansion of Functional CD25+ CD4+ Regulatory T Cells by Antigen-processing Dendritic Cells

2003 ◽  
Vol 198 (2) ◽  
pp. 235-247 ◽  
Author(s):  
Sayuri Yamazaki ◽  
Tomonori Iyoda ◽  
Kristin Tarbell ◽  
Kara Olson ◽  
Klara Velinzon ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Antigen Processing ◽  
Specific Antigen ◽  
Cell Receptor ◽  
Cd4 T Cell

An important pathway for immune tolerance is provided by thymic-derived CD25+ CD4+ T cells that suppress other CD25− autoimmune disease–inducing T cells. The antigen-presenting cell (APC) requirements for the control of CD25+ CD4+ suppressor T cells remain to be identified, hampering their study in experimental and clinical situations. CD25+ CD4+ T cells are classically anergic, unable to proliferate in response to mitogenic antibodies to the T cell receptor complex. We now find that CD25+ CD4+ T cells can proliferate in the absence of added cytokines in culture and in vivo when stimulated by antigen-loaded dendritic cells (DCs), especially mature DCs. With high doses of DCs in culture, CD25+ CD4+ and CD25− CD4+ populations initially proliferate to a comparable extent. With current methods, one third of the antigen-reactive T cell receptor transgenic T cells enter into cycle for an average of three divisions in 3 d. The expansion of CD25+ CD4+ T cells stops by day 5, in the absence or presence of exogenous interleukin (IL)-2, whereas CD25− CD4+ T cells continue to grow. CD25+ CD4+ T cell growth requires DC–T cell contact and is partially dependent upon the production of small amounts of IL-2 by the T cells and B7 costimulation by the DCs. After antigen-specific expansion, the CD25+ CD4+ T cells retain their known surface features and actively suppress CD25− CD4+ T cell proliferation to splenic APCs. DCs also can expand CD25+ CD4+ T cells in the absence of specific antigen but in the presence of exogenous IL-2. In vivo, both steady state and mature antigen-processing DCs induce proliferation of adoptively transferred CD25+ CD4+ T cells. The capacity to expand CD25+ CD4+ T cells provides DCs with an additional mechanism to regulate autoimmunity and other immune responses.

scholarly journals Engineered FVIII-Specific Human T-Effector Cells: Can the T-Cell Receptor Modulate CD4+ T-Helper Phenotypes or Is It Just a “Switch”?

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1417-1417
Author(s):  
Patrick Adair ◽  
Yong Chan Kim ◽  
Kathleen P. Pratt ◽  
David W Scott
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Hemophilia A ◽  
Puget Sound ◽  
Cell Receptor ◽  
Cd4 T Cell ◽  
Dose Titration ◽  
T Helper

Abstract Engineered T cells are a vital component in the armamentarium of cellular therapies. In this presentation, we examine how human CD4+ T cells, genetically engineered to express a T-cell receptor (TCR) specific for a C2 domain epitope of the coagulation protein cofactor FVIII, can be skewed or polarized to different T-helper subsets. Two TCRs were cloned from Th2 and Th17/Th1 phenotyped CD4+ T cells isolated via a tetramer guided epitope mapping (TGEM) technique from a hemophilia A subject after clinical diagnosis of an inhibitor (neutralizing antibody) to FVIII given as replacement therapy. The two TCRs were cloned using a 5’ RACE with semi-nested PCR and transduced via a retroviral vector into healthy non-hemophilia A human donor CD4+ T cells. Based on proliferation and HLA class II tetramer staining data, engineered CD4+ T cells expressing the different cloned TCRs exhibited different avidities for the same C2 peptide (containing the epitope) over a dose titration curve, despite similar levels of TCR expression on the CD4 T-cell surface. IFN-γ, TNF-α, IL-6, and IL-10 cytokine production levels following stimulation with C2 peptide and DR1 antigen presenting cells, as measured by cytokine bead analysis, were significantly greater for the higher avidity TCR, which was cloned from a “Th2” phenotyped CD4+ T-cell clone. Interestingly, neither the engineered CD4+ T cells expressing the Th2 TCR nor the cells expressing the Th17/Th1 TCR produced cytokines characteristic of their respective original parental clones. Rather, they reflected the cytokine profiles of the donor populations used for transduction. These preliminary data led us to investigate how the different avidities of the two cloned TCRs can modulate the T-helper subset skewing/differentiation potential of engineered CD4+T cells. We hypothesized that the TCR is merely a switch that can activate or direct engineered CD4+ T cells to an antigen-specific response that would be skewed to the T-helper phenotypes of the cells prior to TCR transduction. We further hypothesized that this response could be modulated after TCR transduction according to the apparent tetramer avidity of the engineered cells. We successfully skewed the engineered human T-helper cells to Th1, Th2 and Th17 lineages, based on T-helper signature cytokine expression and the transcription factors T-bet, Gata3 and RORγt. Moreover, we observed that TCR transduction into naïve human CD4+ T cells did not itself affect the T-helper subset skewing of the cells. Preliminary experiments showed a trend toward Th2 skewing for the high avidity Th2 CD4+ T cells having an engineered TCR when they were cultured under either Th1 or Th2 polarizing conditions and stimulated with the C2 peptide, compared to the phenotypes obtained following stimulation of polyclonal CD4 T cells with anti-CD3. These studies will improve our designing of engineered TCRs for CD4+T-cell therapy, especially when concerns of T-helper effector function and plasticity are important to clinical outcomes. Supported by NIH RO1-HL061883 (DWS), funding from Bayer and CSL Behring (KPP) and intramural support from NIAID (EMS). We thank Dr. Arthur Thompson (Puget Sound Blood Center) for enrolling patients and we thank all blood donors. Disclosures No relevant conflicts of interest to declare.

scholarly journals CD4+ T cell subsets present stable relationships in their T cell receptor repertoires

2020 ◽  
Author(s):  
Shiyu Wang ◽  
Longlong Wang ◽  
Ya Liu
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
T Cell Receptor ◽  
Cd4 T Cells ◽  
Cell Receptor ◽  
T Cell Subsets ◽  
Cd4 T Cell ◽  
Antigen Specificity ◽  
Sequence Composition

AbstractCD4+ T cells are key components of adaptive immunity. The cell differentiation equips CD4+ T cells with new functions. However, the effect of cell differentiation on T cell receptor (TCR) repertoire is not investigated. Here, we examined the features of TCR beta (TCRB) repertoire of the top clones within naïve, memory and regular T cell (Treg) subsets: repertoire structure, gene usage, length distribution and sequence composition. First, we found that memory subsets and Treg would be discriminated from naïve by the features of TCRB repertoire. Second, we found that the correlations between the features of memory subsets and naïve were positively related to differentiation levels of memory subsets. Third, we found that public clones presented a reduced proportion and a skewed sequence composition in differentiated subsets. Furthermore, we found that public clones led naïve to recognize a broader spectrum of antigens than other subsets. Our findings suggest that TCRB repertoire of CD4+ T cell subsets is skewed in a differentiation-depended manner. Our findings show that the variations of public clones contribute to these changes. Our findings indicate that the reduce of public clones in differentiation trim the antigen specificity of CD4+ T cells. The study unveils the physiological effect of memory formation and facilitates the selection of proper CD4+ subset for cellular therapy.

Age-Related Induction of CD4+ T-Cell Unresponsiveness Is Reversible and Dependant of the Host’s Environment.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3925-3925
Author(s):  
Pedro Horna ◽  
Rahul Chavan ◽  
Jason Brayer ◽  
Ildefonso Suarez ◽  
Eduardo M. Sotomayor
Keyword(s):  
T Cells ◽  
T Cell ◽  
Transgenic Mice ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Cell Compartment ◽  
Memory Phenotype ◽  
Age Related ◽  
And Function

Abstract A large number of CD4+ T-cells from either aged mice or humans display surface markers associated with an activated/memory phenotype. In spite of these changes however, these T-cells have a markedly decreased ability to proliferate and produce IL-2 in response to antigen stimulation in vitro. The cellular and molecular mechanisms involved in this age-related unresponsiveness of the CD4+ T-cell compartment remain poorly understood. Utilizing a well-established experimental system in which transgenic CD4+ T cells specific for a MHC class II restricted epitope of influenza hemagglutinin (HA) are adoptively transferred into non-transgenic recipients, we have previously elucidated important mechanisms involved in the induction and maintenance of CD4+ T-cell tolerance. Our studies were however limited to the analysis of T-cell function in lymphoma bearing young mice (4 to 10 weeks old). Here, we assessed the influence of the aged microenvironment in determining the phenotype and function of antigen-specific T-cells. CD4+ T-cells from young TCR transgenic mice (2 months old) were adoptively transferred into either old (20–24 months) or young (2 months old) non-transgenic mice. Two weeks later, clonotypic and non-clonotypic CD4+ T-cells were isolated from the spleens of these animals and their phenotype and function were determined in vitro. Reminiscent of the age-related changes observed within the normal CD4+ T-cell repertoire, young transgenic T-cells transferred into aged hosts have acquired an activated/memory phenotype but displayed a significant impairment in antigen-specific proliferation and IL-2 production in response to cognate antigen in vitro. These changes were not due to homeostatic proliferation of the transferred T-cells into the relatively lymphopenic aged host. To determine whether the changes observed in “aged” T-cells were reversible or not, we adoptively transfer old T-cells back into young hosts or into control old mice. While old transgenic T-cells transferred into an old environment remained fully unresponsive, the adoptive transfer of the same old T-cells into a young host restored their ability to proliferate and produce IL-2. Surprisingly, these “old” T-cells were able to produce significantly higher levels of IFN-gamma indicative of their memory/effector phenotype. Furthermore, young animals adoptively transferred with “aged” antigen-specific T-cells were now capable of rejecting A20 B-cell lymphomas expressing HA as a model tumor antigen (A20HA). Taking together, factor(s) present in the aged microenvironment are responsible for limiting the effector function of CD4+ T-cells that seem otherwise well equipped to become fully activated if the proper environment is provided (young microenvironment). The potential role of soluble suppressive factors as well as regulatory T-cells (Tregs) in the unresponsiveness observed in the T-cell compartment of aged hosts will be discussed.

scholarly journals Regulatory CD4 T Cells Control the Size of the Peripheral Activated/Memory CD4 T Cell Compartment

2000 ◽  
Vol 164 (7) ◽  
pp. 3573-3580 ◽  
Author(s):  
Oliver Annacker ◽  
Odile Burlen-Defranoux ◽  
Ricardo Pimenta-Araujo ◽  
Ana Cumano ◽  
Antonio Bandeira
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Cell Compartment

scholarly journals Self major histocompatibility complex class I antigens expressed solely in lymphoid cells do not induce tolerance in the CD4+ T cell compartment.

1996 ◽  
Vol 184 (4) ◽  
pp. 1573-1578 ◽  
Author(s):  
R Schulz ◽  
A L Mellor
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Lymphoid Cells ◽  
Cd4 T Cell ◽  
Cell Compartment ◽  
Mhc I ◽  
Mhc Ii ◽  
Histocompatibility Complex ◽  
Self Peptides

Transgenic mice expressing self major histocompatibility complex (MHC) class I (H-2Kb) antigen solely in lymphoid cell lineages do not acquire tolerance to H-2Kb expressed on skin grafts. H-2Kb-specific cytotoxic T cell responses were completely abrogated in these mice, even after they had rejected skin grafts. Moreover, thymocytes expressing T cell receptors that confer H-2Kb reactivity on cytotoxic CD8+ T cells were eliminated. The ability to reject grafts correlated with the presence of a novel population of H-2Kb-reactive CD4+ T cells. At least some of these CD4+ T cells recognize peptides derived from H-2Kb by processing. We conclude that self MHC I antigens induce tolerance in the CD8 T cell compartment via negative selection when expressed exclusively by lymphoid cells. In contrast, tolerance to MHC class II-restricted self peptides derived by processing of such MHC I antigens is not induced in the CD4 T cell compartment. This suggests that effective transfer of self antigens from lymphoid cells to MHC II-positive cells that can process and present them as self peptides to thymocytes or CD4+ T cells does not take place in vivo. Thus, sequestration of self antigens and MHC II molecules in distinct cell types in the thymic microenvironment allows potentially autoreactive and functionally competent CD4+ T cells that recognize cryptic MHC II-restricted self peptides to mature into the peripheral T cell repertoire under normal physiological circumstances.

scholarly journals OP0003 AUTOREACTIVE CD4+ T CELLS AND THEIR TCR REPERTOIRE IN PR3-ANCA ASSOCIATED VASCULITIS

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 1.3-1
Author(s):  
R. Kumar ◽  
N. Yoosuf ◽  
A. Bartoletti ◽  
A. Avik ◽  
B. Raposo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Cd4 T Cells ◽  
Cell Receptor ◽  
Cd4 T Cell ◽  
Proteinase 3 ◽  
Anca Associated Vasculitis ◽  
Cell Clones ◽  
Tcr Repertoire

Background:ANCA-associated vasculitis (AAV) with proteinase 3 (PR3) ANCA is genetically associated with HLA-DP [1], is often relapsing in nature, and has a predisposition for kidneys, lungs and ear-nose-throat involvement [2]. Despite the presence of PR3+ANCA, indicating CD4+T-cell help in the disease, the knowledge about autoreactive CD4+T cells is scarce. Activated T cells have been shown at site of inflammation [3] and involvement of proinflammatory cytokines in circulation is also reported [4, 5].Objectives:Identification of autoreactive T cells may help to identify the drivers of the immune responses and chronicity. We therefore aimed to investigate PR3-specific CD4+T-cell responses in peripheral blood of AAV patients with a focus on both phenotype and T-cell receptor (TCR) repertoires.Methods:The study included sixty-six patients: 26 with active PR3 autoantibody+ AAV, 21 with inactive but PR3+ AAV and 19 with inactive PR3- AAV. In-vitro cultures with PR3 protein were established to assess antigen-specific cytokine responses in a 3-color fluorospot assay. Deep immunophenotyping was performed by flow cytometry. Antigen-responsive CD4+ T cells were isolated and single cell TCRαβ sequences were generated and analyzed from PR3+ AAV patients (n=5) using a previously published protocol [6].Results:PBMCs from AAV patients demonstrated an HLA-DP associated cytokine responses to PR3 stimulation including IFN-γ and IL-10, but not IL-17A. This T-cell autoreactivity was found to be confined to a highly differentiated CD4+ T cell population characterized by perforin and GPR56 expression, implicating a cytotoxic feature of the response. Active disease involved a reduction in expression of several markers associated with cytotoxicity amongst the CD4+GPR56+ T cells. Their frequency was also negatively associated with the doses of prednisolone. A similar phenotype was shared with T cells activated by human cytomegalovirus (HCMV) peptides in the same patient cohort. Single cell sequencing of paired alpha beta T-cell receptors (TCRs) revealed different patterns of gene usage between PR3 and HCMV reactive T cells. Moreover, we could identify shared (public) PR3-reactive T-cell clones between different HLA-DPB1*04:01+ patients.Conclusion:PR3 is an autoantigen which provokes ANCA responses in AAV patients. Our study identified PR3-reactive CD4+ T cells at the level of their phenotype and TCR repertoire. The autoreactive CD4+ T cells, present in both active and inactive disease, implicate chronic antigen exposure and the persistence of long-lived T-cell clones. The presence of public autoreactive clones between HLA-DPB1*04:01+ patients suggests an active role for these cells in pathogenesis of AAV and validates the link with predisposed genotype.References:[1]Lyons PA, Rayner TF, Trivedi S, Holle JU, Watts RA, Jayne DR, et al. Genetically distinct subsets within ANCA-associated vasculitis. New England Journal of Medicine. 2012; 367(3):214-223.[2]Kumar Sharma R, Lövström B, Gunnarsson I, Malmström V. Proteinase 3 autoreactivity in Anti-Neutrophil Cytoplasmic Antibody-associated vasculitis–immunological versus clinical features. Scandinavian Journal of Immunology. 2020:e12958.[3]Wilde B, Thewissen M, Damoiseaux J, van Paassen P, Witzke O, Tervaert JWCJAr, et al. T cells in ANCA-associated vasculitis: what can we learn from lesional versus circulating T cells? 2010; 12(1):204.[4]Hoffmann JC, Patschan D, Dihazi H, Müller C, Schwarze K, Henze E, et al. Cytokine profiling in anti neutrophil cytoplasmic antibody-associated vasculitis: a cross-sectional cohort study. Rheumatology international. 2019; 39(11):1907-1917.[5]Berti A, Warner R, Johnson K, Cornec D, Schroeder D, Kabat B, et al. Circulating Cytokine Profiles and ANCA Specificity in Patients with ANCA-Associated Vasculitis. Arthritis & rheumatology (Hoboken, NJ). 2018; 70(7):1114.[6]Han A, Glanville J, Hansmann L, Davis MM. Linking T-cell receptor sequence to functional phenotype at the single-cell level. Nature biotechnology. 2014; 32(7):684-692.Disclosure of Interests:None declared

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