Homeostatic control of immunity by TCR peptide-specific Tregs

Abstract

Regulation of the immune response is a multifaceted process involving lymphocytes that function to maintain both self tolerance as well as homeostasis following productive immunity against microbes. There are 2 broad categories of Tregs that function in different immunological settings depending upon the context of antigen exposure and the nature of the inflammatory response. During massive inflammatory conditions such as microbial exposure in the gut or tissue transplantation, regulatory CD4+CD25+ Tregs broadly suppress priming and/or expansion of polyclonal autoreactive responses nonspecifically. In other immune settings where initially a limited repertoire of antigen-reactive T cells is activated and expanded, TCR-specific negative feedback mechanisms are able to achieve a fine homeostatic balance. Here I will describe experimental evidence for the existence of a Treg population specific for determinants that are derived from the TCR and are expressed by expanding myelin basic protein-reactive T cells mediating experimental autoimmune encephalomyelitis, an animal prototype for multiple sclerosis. These mechanisms ensure induction of effective but appropriately limited responses against foreign antigens while preventing autoreactivity from inflicting escalating damage. In contrast to CD25+ Tregs, which are most efficient at suppressing priming or activation, these specific Tregs are most efficient in controlling T cells following their activation.

Figure 1

A negative-feedback regulatory mechanism involving CD4⁺ and CD8⁺ Tregs recognizing TCR peptide/MHC complexes. During normal peripheral turnover or following the expansion/contraction phase, MBP-reactive, V_β8.2⁺ CD4⁺ T cells are captured by professional APCs. These APCs process and present distinct TCR V_β8.2 peptides in the context of I-A^u MHC class II and Qa-1^a MHC class Ib molecules for the induction of CD4⁺ and CD8⁺ Tregs, respectively, a process commonly referred to as cross-priming. CD4⁺ Tregs predominantly utilize the TCR V_β14 gene segment, recognize an Fr3 region TCR peptide, and secrete type 1 proinflammatory cytokines, such as IFN-γ, for effective recruitment or activation of CD8⁺ Tregs. CD8⁺ Tregs recognize CDR1/2 region TCR peptide/Qa-1^a complexes on the surface of activated and pathogenic V_β8.2⁺ Th1 cells, resulting in their apoptotic death. Low avidity, slower-reacting Th2 cells that are relatively less susceptible to apoptosis can then eventually expand, resulting in immune deviation of the anti-MBP response at the population level. At this stage, Th2 cell secretion of cytokines such as IL-4 or IL-10 can further enhance the downregulation of the anti-MBP response (41).