TCR Down-Regulation Controls Virus-Specific CD8+ T Cell Responses

Abstract

The CD3γ di-leucine-based motif plays a central role in TCR down-regulation. However, little is understood about the role of the CD3γ di-leucine-based motif in physiological T cell responses. In this study, we show that the expansion in numbers of virus-specific CD8+ T cells is impaired in mice with a mutated CD3γ di-leucine-based motif. The CD3γ mutation did not impair early TCR signaling, nor did it compromise recruitment or proliferation of virus-specific T cells, but it increased the apoptosis rate of the activated T cells by increasing down-regulation of the antiapoptotic molecule Bcl-2. This resulted in a 2-fold reduction in the clonal expansion of virus-specific CD8+ T cells during the acute phase of vesicular stomatitis virus and lymphocytic choriomeningitis virus infections. These results identify an important role of CD3γ-mediated TCR down-regulation in virus-specific CD8+ T cell responses.

TCR Down-Regulation Controls T Cell Homeostasis

“…Seven days after injection, the mice were killed and the TCR-transgenic V␣2 ϩ CD8 ϩ T cells were analyzed. Bone marrow chimeric mice were produced as previously described (32). Briefly, lethally irradiated (12 Gy) C57BL/6 mice were transplanted with bone marrow from congenic WT and CD3␥LLAA mice in a 1:1 ratio.…”

“…Generation of the CD3␥LLAA knock-in and P14LLAA mice strains has recently been described (32). The CD3␥LLAA strain was backcrossed for 10 generations to C57BL/6 mice.…”

“…Accordingly, CD3␥LLAA T cells express 40 -50% more TCR than WT T cells following stimulation with specific pMHC. The increased TCR expression results in stronger TCR signaling and increased activation-induced cell death in CD3␥LLAA T cells compared with WT T cells during acute virus infections (32).…”

Signaling Mechanisms that Balance Anti-viral, Auto-reactive, and Antitumor Potential of Low Affinity T Cells

“…There is evidence suggesting that TCR down-modulation is absolutely required for T cell activation [42,43]. However, most of the studies show that this process prevents T cell hyperactivation by terminating TCR signal transduction [44][45][46][47][48][49]. PD-1 associates to the TCR at the immunological synapse and controls its signal transduction as well as its presence on the T cell surface [39,41].…”

“…Character Species Systemic Lupus Erythematosus Susceptibility Human [44] Lupus Nephritis Susceptibility Human [45] Rheumatoid Arthritis Susceptibility Human [46] Ankylosing Spondylitis Susceptibility Human [47] Cbl-b -/-Type I diabetes Susceptibility Rat [48] Multisystem autoimmune disease Spontaneous Mouse [49] Tumour rejection Spontaneous Mouse [50] Experimental Autoimmune Encephalomyelitis Susceptibility Mouse [22] …”