Effect of chronic viral infection on epitope selection, cytokine production, and surface phenotype of CD8 T cells and the role of IFN-gamma receptor in immune regulation.
Regulation of CD8 T cell responses in chronic viral infections is not well understood. In this study, we have compared the CD8 T cell responses to immunodominant and subdominant epitopes during an acute and a chronic lymphocytic choriomeningitis virus (LCMV) infection in mice. The epitope hierarchy of the primary CD8 T cell response was similar in acute and chronic LCMV infections. However, strikingly, the epitope hierarchy of the primary CD8 T cell response was conserved in the T cell memory only in an acute but not in a chronic LCMV infection. Interestingly, in an acute infection, increasing the viral dose caused significant changes in the epitope hierarchy of the LCMV-specific memory CD8 T cell pool, with no effect on the primary CD8 T cell response. Functional and phenotypic analyses revealed that exposure of CD8 T cells to extended periods of antigenic stimulation could lead to long-term defects in cytokine production and alteration in expression of cell surface L-selectin (CD62L). Whereas expression of CD44 was minimally altered, a greater proportion of LCMV-specific memory CD8 T cells were CD62L(low) in mice that have recovered from a chronic LCMV infection, compared with acutely infected mice. Mechanistic studies showed that IFN-gammaR deficiency altered the epitope hierarchy of the pool of LCMV-specific memory CD8 T cells without significantly affecting the immunodominance of the primary CD8 T cell response in an acute infection. Taken together, these findings should further our understanding about the regulation of T cell responses in human chronic viral infections.
Tewari
Kavita
K
Department of Pathobiological Sciences, University of Wisconsin, Madison, WI 53706.
Sacha
Jonah
J
Gao
Xiaoyan
X
Suresh
M
M
D000208:Acute Disease; D000818:Animals; D000081242:B-Cell Lymphoma 3 Protein; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002908:Chronic Disease; D016207:Cytokines / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D018984:Epitopes, T-Lymphocyte / Q000096:biosynthesis* / Q000378:metabolism; D016056:Immunodominant Epitopes / Q000096:biosynthesis / Q000378:metabolism; D007156:Immunologic Memory; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000378:metabolism / Q000502:physiology*; D008216:Lymphocytic Choriomeningitis / Q000276:immunology*; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis; D051560:Proto-Oncogene Proteins c-bcl-6; D017471:Receptors, Interferon / Q000378:metabolism / Q000502:physiology*; D014157:Transcription Factors / Q000096:biosynthesis; D000096743:Interferon gamma Receptor
D000081242:B-Cell Lymphoma 3 Protein; D016207:Cytokines; D004268:DNA-Binding Proteins; D018984:Epitopes, T-Lymphocyte; D016056:Immunodominant Epitopes; D007371:Interferon-gamma; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051560:Proto-Oncogene Proteins c-bcl-6; D017471:Receptors, Interferon; D014157:Transcription Factors; D000096743:Interferon gamma Receptor; C000631344:BCL3 protein, human; C000631345:Bcl3 protein, mouse