Quantitative impact of thymic selection on Foxp3 ⁺ and Foxp3 ⁻ subsets of self-peptide/MHC class II-specific CD4 ⁺ T cells

Abstract

It is currently thought that T cells with specificity for self-peptide/ MHC (pMHC) ligands are deleted during thymic development, thereby preventing autoimmunity. In the case of CD4 + T cells, what is unclear is the extent to which self-peptide/MHC class II (pMHCII)-specific T cells are deleted or become Foxp3 + regulatory T cells. We addressed this issue by characterizing a natural polyclonal pMHCII-specific CD4 + T-cell population in mice that either lacked or expressed the relevant antigen in a ubiquitous pattern. Mice expressing the antigen contained one-third the number of pMHCII-specific T cells as mice lacking the antigen, and the remaining cells exhibited low TCR avidity. In mice lacking the antigen, the pMHCII-specific T-cell population was dominated by phenotypically naive Foxp3− cells, but also contained a subset of Foxp3 + regulatory cells. Both Foxp3 − and Foxp3 + pMHCII-specific T-cell numbers were reduced in mice expressing the antigen, but the Foxp3 + subset was more resistant to changes in number and TCR repertoire. Therefore, thymic selection of self-pMHCII-specific CD4 + T cells results in incomplete deletion within the normal polyclonal repertoire, especially among regulatory T cells.ccording to clonal selection theory, self-reactive lymphocytes are deleted during development, thereby ensuring immunological tolerance to self tissues (1). In the case of T cells, this process occurs in the thymus where developing thymocytes with randomly generated T-cell antigen receptor (TCR) specificities are educated on an array of self-peptide/MHC (pMHC) ligands (2). In the simplest form of this model, thymocytes receiving strong TCR signals are deleted, thereby purging the repertoire of any cells with self-pMHC specificity. The significance of this mechanism of central tolerance has been substantiated by studies demonstrating that impairment of antigen presentation in the thymus can lead to autoimmunity (3, 4). Nevertheless, the clonal deletion rule is challenged by the wellknown observation that immunization with certain self-peptides can induce autoimmunity, indicating that at least some responsive self-pMHC-specific T cells routinely exist in the repertoire (5).Another intriguing exception to the clonal deletion rule is presented by regulatory T (Treg) cells, a suppressive subset of CD4 + T cells defined by expression of the Foxp3 transcription factor (6, 7). Whereas some Treg cells are induced from conventional T cells during immune responses (iTreg), most are socalled natural regulatory T (nTreg) cells, which arise directly in the thymus much like naive CD4 + T cells (8). Studies have shown that nTreg cells develop as a consequence of the type of high-affinity TCR-self-pMHCII interaction that was thought to cause clonal deletion (9). Moreover, extensive TCR sequencing studies of Treg and non-Treg populations have indicated that, whereas the specificities of these repertoires overlap, Treg cell specificity is biased toward self-pMHCII ligands (10, 11).These findings lead to the question of why some sel...

Optimal T-cell receptor affinity for inducing autoimmunity

“…This idea is consistent with the relatively low incidence of autoimmunity in the general population; 3% of the human population suffers from some form of autoimmunity (48). Nevertheless, an individual can probably cope with a small number of high-affinity peripheral T cells and still be considered functionally tolerant, allowing negative selection to be less than perfect, which seems to be the case (49,50). Recent computational studies (51) propose that an immune or autoimmune response requires a minimum (quorum) number of antigen-specific T cells.…”

Distinct Graft-Specific TCR Avidity Profiles during Acute Rejection and Tolerance

“…Although these two models represent two physiologically different settings, the data were indistinguishable and therefore combined where noted. 2W- and OVA-reactive T cell populations are rare in naive, antigen-inexperienced mice (Moon et al, 2011), such that in all experiments, T cell enrichment by negative selection was first performed to increase the frequency of multimer-binding T cells during subsequent flow cytometric analysis. Transplantation tolerance was induced with a combination of anti-CD154 and donor splenocyte transfusion (DST) at the time of transplantation.…”

“…For these other specificities, resistance to avidity maturation may be epigenetically imprinted, similar to T cell-intrinsic hyporesponsiveness, which makes cells resistant to secondary encounter of antigen (Philip et al, 2017; Schietinger et al, 2012), or may be constrained by regulatory cells distinct from classical Tregs. Studies of T cells in tumor microenvironments that are deemed dysfunctional and of self-specific T cells (Black et al, 2014; Kuball et al, 2009; Malhotra et al, 2016; Moon et al, 2011; Soong et al, 2014; Souders et al, 2007; Wong et al, 2008; Yu et al, 2015) have also revealed that many of these cells are low avidity at the population level, supporting the idea that tolerance, whether spontaneously acquired in the tumor microenvironment or upon self-antigen encounter or, as we show in this study, therapeutically induced by costimulation blockade therapy, may be simultaneously enforced through multiple mechanisms, one of which being the preservation of low-avidity repertoire for the relevant antigen.…”

Immunologic characteristics of HIV‐infected individuals who make broadly neutralizing antibodies

“…These cells, which are termed natural CD4 + Treg cells (nTregs) (reviewed in 225), respond to antigenic stimulation by differentiating into effector Treg cells 226. There are nTreg cells with specificity for both self and foreign antigens, although the ratio of antigen‐specific FoxP3 + to FoxP3 − cells is higher for the former, enabling more stringent control of responses to autoantigens 227. FoxP3 expression can also be induced in FoxP3 − naive CD4 + T cells in the periphery in response to antigenic stimulation in the presence of IL‐2 and TGFβ,228, 229 resulting in the generation of induced (i)Treg cells.…”