Cutting Edge: Dual TCRα Expression Poses an Autoimmune Hazard by Limiting Regulatory T Cell Generation

Abstract

Despite accounting for 10–30% of the T cell population in mice and humans, the role of dual TCR-expressing T cells in immunity remains poorly understood. It has been hypothesized that dual TCR T cells pose an “autoimmune hazard” by allowing self-reactive TCRs to escape thymic selection. We revisited this hypothesis using the NOD murine model of type 1 diabetes (T1D). We bred NOD mice hemizygous at both TCRα and β (TCRα+/− β+/−) loci, rendering them incapable of producing dual TCR T cells. We found that the lack of dual TCRα expression skewed the insulin-specific thymocyte population toward greater regulatory T (Treg) cell commitment, resulting in a more tolerogenic Treg to conventional T (Tconv) cell ratio and protection from diabetes. These data support a novel hypothesis by which dual TCR expression can promote autoimmunity by limiting agonist selection of self-reactive thymocytes into the Treg cell lineage.

Dual TCR T Cells: Identity Crisis or Multitaskers?

“…Here, strongly self-reactive CD4 + T cells may be clonally deleted or undergo agonist selection to become T reg cells (77). In NOD mice lacking dual TCRa expression (TCRa +/2 ), we observed an increased ratio of T reg cells to SP cells in the thymus and less apoptosis among the signaled CD4SP population, indicating increased T reg commitment and decreased clonal deletion (76). This suggests that dual TCRa-expressing T reg cells should be rare, yet human thymic and peripheral T cells expressing both Va12 and Va2 TCRs were three times as frequent in the CD25 + T reg cellenriched population versus the CD25 2 population, leading to the interpretation that dual TCRa expression may be common in T reg cells (78).…”

“…Agonist selection. Recently we demonstrated that dual TCR expression might also limit agonist selection of thymic T reg cells (76). Thymocytes that survive positive and negative selection in the cortex migrate to the medulla as single positive (SP) thymocytes where they encounter a new assemblage of self-peptide-MHC.…”

“…Therefore, in the normal state, phenotypic allelic exclusion appears competent to maintain high-fidelity clonal deletion of the majority of potentially hazardous self-reactive dual TCRa thymocytes (85). The seemingly contradictory observations regarding the impact of dual TCRa expression on agonist selection of T reg cells further confounds our understanding of how dual TCRa T cells contribute to autoimmunity and emphasizes the need for more direct evidence demonstrating how dual TCRa expression affects T reg cell lineage commitment (76,78).…”

Endogenous co-expression of two T cell receptors promotes lymphopenia-induced proliferation via increased affinity for self-antigen

“…Previous examinations of mice genetically deficient for dual TCR expression have not identified overt T cell compartment defects, indicating that dual TCR expression is not absolutely required for T cell development, homeostasis, or function. However, this does not preclude important effects of dual TCR expression on the development, composition, or function of the T cell repertoire.…”

Poor Quality Vβ Recombination Signal Sequences Enforce TCRβ Allelic Exclusion by Limiting the Frequency of Vβ Recombination

“…The predominant, long-standing theory is that the expression of only one type (specificity) of AgR by T and B cells suppresses autoimmunity by ensuring negative selection of cells expressing a self-reactive receptor (Brady et al, 2010a;Heath and Miller, 1993;Padovan et al, 1993). Consistent with this hypothesis, expression of a second endogenous AgR enables cells bearing a transgenic autoreactive AgR to evade negative selection (Auger et al, 2012;Iliev et al, 1994;Sarukhan et al, 1998;Zal et al, 1996), and biallelic TCRα expression potentiates autoimmune diabetes in the NOD mouse model (Schuldt et al, 2017). Our findings suggest new avenues for investigation.…”