Expansion of dysfunctional Tim-3-expressing effector memory CD8+ T cells during simian immunodeficiency virus infection in rhesus macaques.

Abstract

The T cell Ig- and mucin domain-containing molecule-3 (Tim-3) negative immune checkpoint receptor demarcates functionally exhausted CD8(+) T cells arising from chronic stimulation in viral infections like HIV. Tim-3 blockade leads to improved antiviral CD8(+) T cell responses in vitro and, therefore, represents a novel intervention strategy to restore T cell function in vivo and protect from disease progression. However, the Tim-3 pathway in the physiologically relevant rhesus macaque SIV model of AIDS remains uncharacterized. We report that Tim-3(+)CD8(+) T cell frequencies are significantly increased in lymph nodes, but not in peripheral blood, in SIV-infected animals. Tim-3(+)PD-1(+)CD8(+) T cells are similarly increased during SIV infection and positively correlate with SIV plasma viremia. Tim-3 expression was found primarily on effector memory CD8(+) T cells in all tissues examined. Tim-3(+)CD8(+) T cells have lower Ki-67 content and minimal cytokine responses to SIV compared with Tim-3(-)CD8(+) T cells. During acute-phase SIV replication, Tim-3 expression peaked on SIV-specific CD8(+) T cells by 2 wk postinfection and then rapidly diminished, irrespective of mutational escape of cognate Ag, suggesting non-TCR-driven mechanisms for Tim-3 expression. Thus, rhesus Tim-3 in SIV infection partially mimics human Tim-3 in HIV infection and may serve as a novel model for targeted studies focused on rejuvenating HIV-specific CD8(+) T cell responses.

• Authors: Tsuyoshi Fujita, Benjamin J Burwitz, Glen M Chew, Jason S Reed, Reesab Pathak, Elizabeth Seger, Kiera L Clayton, James M Rini, Mario A Ostrowski, Naoto Ishii, Marcelo J Kuroda, Scott G Hansen, Jonah B Sacha, Lishomwa C Ndhlovu
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 193 Issue 11 Pg. 5576-83 (Dec 01 2014) ISSN: 1550-6606 [Electronic] United States
• PMID: 25348621 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 by The American Association of Immunologists, Inc.

Chemical References

• HAVCR2 protein, human
• Hepatitis A Virus Cellular Receptor 2
• Membrane Proteins
• Programmed Cell Death 1 Receptor

Topics

• Acquired Immunodeficiency Syndrome (immunology, therapy)
• Amino Acid Sequence
• Animals
• CD8-Positive T-Lymphocytes (immunology, virology)
• Cell Proliferation
• Cells, Cultured
• Cytotoxicity, Immunologic
• Disease Models, Animal
• Gene Expression Regulation
• Hepatitis A Virus Cellular Receptor 2
• Humans
• Immunologic Memory
• Immunotherapy (methods)
• Macaca mulatta
• Membrane Proteins (genetics, metabolism)
• Molecular Sequence Data
• Molecular Targeted Therapy
• Programmed Cell Death 1 Receptor (metabolism)
• Simian Acquired Immunodeficiency Syndrome (immunology, therapy)
• Simian Immunodeficiency Virus (physiology)
• Viral Load
• Virus Replication