Development and homeostasis of T cell memory in rhesus macaque.
The rhesus macaque (RM) is a critical animal model for studies of viral pathogenesis and immunity, yet fundamental aspects of their cellular immune response remain poorly defined. One such deficiency is the lack of validated phenotypic signatures for their naive and memory T cell subsets, and the resultant unavailability of accurate information on their memory T cell development, homeostasis, and function. In this study, we report a phenotypic paradigm allowing definitive characterization of these subsets and their comprehensive functional analysis. Naive T cells are optimally delineated by their homogeneous CD95(low)CD28(high)beta(7) integrin(int) (CD4+) or CD95(low)CD28(int)CD11a(low) (CD8+) phenotypes. This subset 1) was present in blood and secondary lymph tissues, but not effector sites; 2) vastly predominated in the fetal/neonatal immune system, but rapidly diminished with postnatal age; 3) lacked IFN-gamma production capability, and specific responses to RM CMV; and 4) demonstrated low in vivo proliferative activity. CD4+ and CD8+ memory subsets were CD95(high), but otherwise phenotypically heterogeneous and included all IFN-gamma production, RM CMV-specific responses, effector site T cells, and demonstrated high in vivo proliferative activity ( approximately 10 times the naive subset). These analyses also revealed the RM "effector memory" subset within the overall memory population. This population, best defined by lack of CD28 expression, contained the majority of RM CMV-specific cells, was highly enriched in extralymphoid effector sites, and comprised an increasing proportion of total memory cells with age. The effector memory subset demonstrated similar in vivo proliferative activity and survival as CD28+ "central memory" T cells, consistent with independent homeostatic regulation.
Pitcher
Christine J
CJ
Vaccine and Gene Therapy Institute, Oregon Regional Primate Research Center, Oregon Health and Science University, West Campus, 505 NW 185th Avenue, Beaverton, OR 97006, USA.
Hagen
Shoko I
SI
Walker
Joshua M
JM
Lum
Richard
R
Mitchell
Bridget L
BL
Maino
Vernon C
VC
Axthelm
Michael K
MK
Picker
Louis J
LJ
D000367:Age Factors; D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D000956:Antigens, Viral / Q000276:immunology; D018106:CD28 Antigens / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000276:immunology; D005260:Female; D006706:Homeostasis; D007156:Immunologic Memory; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000096:biosynthesis; D007700:Kinetics; D008213:Lymphocyte Activation; D008221:Lymphoid Tissue / Q000276:immunology; D008253:Macaca mulatta / Q000276:immunology*; D008297:Male; D016176:T-Lymphocyte Subsets / Q000145:classification / Q000276:immunology*
D000945:Antigens, Differentiation, T-Lymphocyte; D000956:Antigens, Viral; D018106:CD28 Antigens; D007371:Interferon-gamma