T cells maintain an exhausted phenotype after antigen withdrawal and population reexpansion

 Daniel T Utzschneider, Amandine Legat, Silvia A Fuertes Marraco, Lucie Carrié, Immanuel Luescher, Daniel E Speiser & Dietmar Zehn, Nat Immunol. 2013 Jun;14(6):603-10.

Speaker: Chi-Ting Hsieh (謝其庭)                     Time: 15:00~16:00, Nov. 27, 2013

Commentator: Dr. Li-Jin Hsu (徐麗君 老師)     Place: Room 601

Abstract:

Pathogens use various strategies to escape from host immune defense and thus establish chronic infection. In this context, repeated stimulation by pathogen antigens and prolonged exposure to inflammation result in T cell exhaustion. Exhausted T cells are characterized by impaired effector functions, decreased cytokine production, and upregulation of many inhibitory receptors. Previous studies indicate that T cells acquiring this exhausted phenotype fail to control pathogen infection and are eventually senescent or deleted. In this study, however, the authors found some memory cell-like characteristics of the so-called exhausted T cells. They transferred the CD8⁺ T cells with the exhausted phenotype from mice chronically infected with lymphocytic choriomeningitis virus (LCMV) to naïve mice. After restimulation of the recipient mice with LCMV, some virus-specific donor T cells reexpanded therein. The cell reexpansion was not due to thymus-derived naïve T cells from the donors. Notably, the reexpanded donor T cells were able to differentiate into effector cells that control virus infection and exert antigen-specific cytotoxicity. More surprisingly, after antigen withdrawal, virus restimulation and cell reexpansion, the donor T cells maintained low cytokine production and high expression of exhaustion markers, suggesting that such memory-like cells stably pass their exhausted phenotype to daughter cells. The authors proposed a new idea that at least some of exhausted T cells retain the potential of reexpansion and support effector functions; meanwhile their inherited exhausted phenotype may prevent unfavorable immunological pathology during chronic infection. Therefore, modulation of the exhausted T cells will be a good strategy for control of chronic infection and for cancer immunotherapy.

References:

1          Salek-Ardakani, S. & Schoenberger, S. P. (2013) T cell exhaustion: a means or an end? Nature immunology 14, 531-533.

2          Wherry, E. J., Barber, D. L., Kaech, S. M., Blattman, J. N. & Ahmed, R. (2004) Antigen-independent memory CD8 T cells do not develop during chronic viral infection. Proceedings of the National Academy of Sciences of the United States of America 101, 16004-16009.