Activated and memory CD8+ T cells can be distinguished by their cytokine profiles and phenotypic markers.
Dissecting the mechanisms of T cell-mediated immunity requires the identification of functional characteristics and surface markers that distinguish between activated and memory T lymphocytes. In this study, we compared the rates of cytokine production by virus-specific primary and memory CD8+ T cells directly ex vivo. Ag-specific IFN-gamma and TNF-alpha production by both primary and long-term memory T cells was observed in </=60 min after peptide stimulation. Although the on-rate kinetics of cytokine production were nearly identical, activated T cells produced more IFN-gamma, but less TNF-alpha, than memory T cells. Ag-specific cytokine synthesis was not a constitutive process and terminated immediately following disruption of contact with peptide-coated cells, demonstrating that continuous antigenic stimulation was required by both T cell populations to maintain steady-state cytokine production. Upon re-exposure to Ag, activated T cells resumed cytokine production whereas only a subpopulation of memory T cells reinitiated cytokine synthesis. Analysis of cytokine profiles and levels of CD8, LFA-1, and CTLA-4 together revealed a pattern of expression that clearly distinguished in vivo-activated T cells from memory T cells. Surprisingly, CTLA-4 expression was highest at the early stages of the immune response but fell to background levels soon after viral clearance. This study is the first to show that memory T cells have the same Ag-specific on/off regulation of cytokine production as activated T cells and demonstrates that memory T cells can be clearly discriminated from activated T cells directly ex vivo by their cytokine profiles and the differential expression of three well-characterized T cell markers.
Slifka
M K
MK
Department of Neuropharmacology, The Scripps Research Institute, La Jolla, CA 92037, USA. mslifka@scripps.edu
Whitton
J L
JL
D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000378:metabolism; D000956:Antigens, Viral / Q000276:immunology; D015415:Biomarkers / Q000032:analysis; D016827:CD8 Antigens / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D060908:CTLA-4 Antigen; D002999:Clone Cells; D016207:Cytokines / Q000096:biosynthesis*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D018796:Immunoconjugates; D007156:Immunologic Memory; D016130:Immunophenotyping; D008213:Lymphocyte Activation; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism* / Q000821:virology
D015703:Antigens, CD; D000943:Antigens, Differentiation; D000956:Antigens, Viral; D015415:Biomarkers; D016827:CD8 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D018796:Immunoconjugates; D016169:Lymphocyte Function-Associated Antigen-1; D000069594:Abatacept