Opposing peripheral fates of tissue‐restricted self antigen‐specific conventional and regulatory CD4⁺ T cells

Abstract

The development of self antigen‐specific T cells is influenced by how the self antigen is expressed. Here, we created a mouse in which a model self antigen is conditionally expressed in different tissue environments. Using peptide:MHCII tetramer‐based cell enrichment methods, we examined the development of corresponding endogenous self antigen‐specific CD4+ T cell populations. While ubiquitous self antigen expression resulted in efficient deletion of self antigen‐specific T cells in the thymus, some tissue‐restricted expression patterns resulted in partial deletion of the population in peripheral lymphoid organs. Deletion specifically affected Foxp3− conventional T cells (Tconv) with a bias towards high avidity TCR expressing cells in the case of thymic, but not peripheral deletion. In contrast, Foxp3+ Treg exhibited elevated frequencies with increased TCR avidity. T cells surviving deletion were functionally impaired, with Tconv cells exhibiting more impairment than Tregs. Collectively, our results illustrate how postthymic recognition of tissue‐restricted self antigens results in opposing developmental fates for Tconv and Treg cell subsets.

Lung injury induces a polarized immune response by self antigen-specific Foxp3+regulatory T cells

“…Expanded self antigen-specific Tregs were able to suppress 2W:I-A b -specific Tconv cells during subsequent immunization with peptide, but interestingly, the global ablation of Tregs did not lead to spontaneous activation and expansion of 2W:I-A b -specific Tconv populations during acute tissue injury. While this may seem to contradict our current model of steady state Treg-mediated tolerance of self antigen-specific T cells 2,28 , it is quite possible that the 2W:I-A b -specific Tconv cells are also under additional intrinsic mechanisms of regulation such as quiescence, anergy, or exhaustion, perhaps imprinted by their earlier continuous suppression from Tregs, a topic that remains to be explored. However, global Treg ablation has previously been shown to result in the rapid onset of systemic autoimmunity 37 , so other self antigenspecific Tconv cells are presumably not under the same level of restraint.…”

“…We have previously reported the generation of a conditional transgenic mouse which, in the presence of Cre recombinase, expresses a Universal Self Antigen (USA) consisting of two model I-A b -restricted CD4 + T cell epitopes, 2W and gp66, embedded within a membrane-bound form of chicken ovalbumin (OVA) 28 . Crossing these USA mice to CC10-Cre transgenic mice results in USA antigen expression restricted to lung epithelial cells via the Clara cell (CC10) promoter.…”

“…Crossing these USA mice to CC10-Cre transgenic mice results in USA antigen expression restricted to lung epithelial cells via the Clara cell (CC10) promoter. We can directly track and characterize lung self antigen-specific CD4 + T cells in the mature peripheral repertoire of these CC10-Cre x USA mice ( CC10-USA ) via the use of 2W:I-A b , gp66:I-A b , or OVA:I-A b tetramers 28,30 . As reported earlier, naïve 2W:I-A b -specific T cells are present in reduced numbers compared to wildtype ( WT ) littermates, slightly enriched for Foxp3 expression, and absent in the lung parenchyma, demonstrating the effects of steady state tolerance on this self antigen-specific T cell population (data not shown).…”

“…The presence of abundant self antigen-specific T cells in the mature peripheral immune repertoire poses a constant threat for autoimmunity 5,44 . In their steady state, these T cells are heavily regulated by various mechanisms of tolerance that have been shown to limit priming and development into pathogenic autoreactive effector cells 2,4,28,45 . However, it is unclear how self antigen-specific T cell populations actually respond to recognition of self antigen that occurs in the context of acute inflammation and tissue damage that could precipitate an autoreactive immune response if normal tolerance mechanisms fail.…”

“…Our lab has developed the use of peptide:MHC tetramer reagents and model antigen-bearing mice to rigorously analyze how endogenous self antigen-specific T cell populations are regulated in the steady state in a tissue specific manner 2,28 . Here, we leveraged the advantages of our experimental systems to directly address how immune-mediated lung injury in these mice leads to activation of endogenous self antigenspecific CD4 + T cells.…”