The Impact of MHC Class I Dose on Development and Maintenance of the Polyclonal Naive CD8+ T Cell Repertoire

Abstract

Naive CD8+ T cell survival in the periphery is critically dependent on tonic TCR signaling through peptide + MHC class I (MHCI) recognition; however, little is known about how natural variation in MHCI levels impacts the naive CD8+ T cell repertoire. Using mice that are hemizygous or homozygous for a single MHCI allele, we showed that despite a reduction in peripheral CD8+ T cell numbers of ∼50% in MHCI hemizygous mice, MHCI levels had no notable impact on the rate of thymic generation or emigration of CD8 single-positive T cells. Moreover, the peripheral T cell repertoire in hemizygous mice showed selective retention of T cell clonotypes with a greater competitive advantage as evidenced by increased expression of CD5 and IL-7Rα. The qualitative superiority of CD8+ T cells retained in hemizygous mice was also seen during influenza A virus infection, in which epitope-specific CD8+ T cells from hemizygous mice had a higher avidity for pMHCI and increased cytokine polyfunctionality, despite a reduced response magnitude. Collectively, this study suggests that natural variation in MHCI expression levels has a notable and biologically relevant impact on the maintenance, but not generation, of the naive CD8+ T cell repertoire.

Development of mouse models with restricted HLA-B∗57:01 presentation for the study of flucloxacillin-driven T-cell activation and tolerance in liver injury

“…Of note, drug-naive Tg/KO animals had approximately 3 times less total splenic CD8 + T cells than Tg, while CD4 + T-cell and natural killer cell levels were comparable ( Fig 3 , C ). Low frequency of CD8 + T cells could be associated with the lack of mMHC-I expression 26 ( Fig 3 , D ). In addition, although HLA expression was enhanced 0.5–3-fold in Tg/KO versus Tg cells ( Fig 3 , E ), the Tg/KO HLA mean fluorescence intensity (MFI) was 4–8.5 times lower than the H2-K b MFI on Tg or WT cells ( Fig 3 , F ).…”

“…To focus on exclusive presentation of FLX epitopes by HLA-B*57:01,we adopted the Tg/KO strain. The weaker drug response observed in Tg/KO mice compared to Tg mice could be attributed to fewer drug-specific CD8 + T cells due to lower peripheral CD8 + T-cell levels in H2-K b D b KO mice, 26 , 33 , 34 and a diminished density of total class I molecules. However, studies showing that TCR-Vβ diversity as well as the rate of thymic generation/egress of CD8 + T cells are not affected by the lack of H2-K b D b 26 , 34 would suggest that the low numbers of circulating FLX-reactive CD8 + T cells in Tg/KO are due to an impairment in the cell maintenance rather than their generation.…”

“…The weaker drug response observed in Tg/KO mice compared to Tg mice could be attributed to fewer drug-specific CD8 + T cells due to lower peripheral CD8 + T-cell levels in H2-K b D b KO mice, 26 , 33 , 34 and a diminished density of total class I molecules. However, studies showing that TCR-Vβ diversity as well as the rate of thymic generation/egress of CD8 + T cells are not affected by the lack of H2-K b D b 26 , 34 would suggest that the low numbers of circulating FLX-reactive CD8 + T cells in Tg/KO are due to an impairment in the cell maintenance rather than their generation. Factors limiting the expansion of FLX-reactive CD8 + T-cell response could be the absence of FLX-reactive WT (HLA − ) T cells acting as helper cells and/or the presence of CD4 + Treg cells.…”

CD5 levels reveal distinct basal T‐cell receptor signals in T cells from non‐obese diabetic mice

“…A recent study shows that low levels of MHC-I expression can result in the preferential accumulation of CD8 + T cells expressing higher levels of CD5. 56 As B6 g7 and NOD mice carry the same MHC locus, potential differences in MHC-I expression may be driven by polymorphisms in B2m. 57 However, we find that the difference in CD5 levels persists in competitive bone marrow chimeras where cells of B6 g7 and NOD origin coexist in the same environment and are thus exposed to the same level of MHC.…”

Transgenic murine models for the study of drug hypersensitivity reactions linked to HLA-I molecules

“…Therefore, to gain knowledge on mechanisms leading to FLX-DILI when drug is presented by HLA-B:57:01, our group generated a strain that exclusively expresses the human allele [HLA Tg/ H2-K b D b KO mice (Tg/KO)] [ 27 ▪ ]. These animals had decreased numbers of CD8+ T cells compared to HLA Tg animals due to the H2-K b D b deletion [ 28 ] but increased expression of the HLA transgene per cell [ 6 ▪ ], thereby resulting in enrichment of drug-reactive T cells in the CD8+ T cell repertoire as seen in other models for nondrug antigens [ 29 ]. Tg/ KO mice treated with FLX and aCD4 Ab had increased levels of drug-induced PD1+CD8+ T cells in both lymphatic organs and liver (Fig.…”