Transcription factor T-bet represses expression of the inhibitory receptor PD-1 and sustains virus-specific CD8⁺ T cell responses during chronic infection

Charlly Kao, et al. Nature immunology (2011) 12:663-672

Speaker: Pin-Hung Lin (林品宏)                                  Time: 14:00~15:00 Sep, 14, 2011

Commentator: Yao Chang, Ph.D. (張堯 老師)            Place: Room 601

Abstract

During chronic viral infections, CD8⁺ T cells become exhausted and fail to control viral replication. High expression of programmed death 1 (PD-1), an inhibitory receptor belongs to CD28-CTLA-4 family, results in T cell exhaustion, and blockade of PD-1 pathway enhances T cell responses¹. However, the transcriptional regulation of PD-1 in exhausted CD8⁺ T cells remains unclear. Using lymphocytic chorimeningitis virus (LCMV) clone 13 to infect mice could induce 2 to 3 months of viremia and CD8⁺ T cell exhaustion, which mimics chronic viral infections, particularly like HBV, HCV, and HIV in humans². In the present study, they found that the level of T-bet in virus-specific CD8⁺ T cells from mice infected with clone 13 was decreased compared with that from mice infected with Armstrong strain of LCMV, which was cleared within 10 days. The expression of T-bet was negatively correlated with that of PD-1 in CD8⁺ T cells. The high level of PD-1 in LCMV-infected T-bet-knockout mice led to lower CD8⁺ T cell responses and higher viral loads. They further found that T-bet was a transcriptional repressor that down-regulated the expressions of PD-1 and other inhibitory receptors. Adoptive transfer of CD8⁺ T cells over-expressing T-bet into mice infected with LCMV clone 13 resulted in lower expression of PD-1 and restored functions in CD8⁺ T cells. Collectively, these results show that T-bet sustains virus-specific CD8⁺ T cell responses by repressing the expression of PD-1.

References:

1.      Barber, D.L. et al. Restoring function in exhausted CD8⁺ T cells during chronic viral infection. Nature (2006) 439:682-687.

2.      Elizabeth B. Wilson, David G. Brooks .Translating insights from persistent LCMV infection into anti-HIV immunity. Immunologic Research (2010) 48:3-13.