On the Self-Referential Nature of Naive MHC Class II-Restricted T Cells

Abstract

The use of mutant mice expressing a normal MHC class II molecule surface level but a severely restricted self-peptide diversity (H-2Mα−/−) previously revealed that T cells carrying the Eα52–68–I-Ab complex-specific 1H3.1 TCR rely on self-peptide(s) recognition for both their peripheral persistence in irradiated hosts and their intrathymic positive selection. Here, we identify Eα52–68 structurally related self-peptide(s) as a major contributor to in vivo positive selection of 1H3.1 TCR-transgenic thymocytes in I-Ab+/I-Eα− mice. This is demonstrated by the drastic and specific reduction of the TCR high thymocyte population in 1H3.1 TCR-transgenic (Tg) mice treated with the Eα52–68–I-Ab complex-specific Y-Ae mAb. Self-peptide(s) recognition is also driving the maturation of T cells carrying a distinct MHC class II-restricted specificity (the Eα6 αβ TCR), since positive selection was also deficient in Eα6 TCR Tg H-2Mα−/− thymi. Such a requirement for recognition of self-determinants was mirrored in the periphery; Eα6 TCR Tg naive T cells showed an impaired persistence in both H-2Mα−/− and I-Abβ−/− irradiated hosts, whereas they persisted and slowly cycled in wild-type recipients. This moderate self-peptide(s)-dependent proliferation was associated with a surface phenotype intermediate between those of naive and activated/memory T cells; CD44 expression was up-regulated, but surface expression of other markers such as CD62L remained unaltered. Collectively, these observations indicate that maturation and maintenance of naive MHC class II-restricted T cells are self-oriented processes.