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*
Vaccine and Gene Therapy Institute, Oregon Regional Primate Research Center, Oregon Health and Science University, West Campus, Beaverton, OR 97006; and
BD Biosciences, San Jose, CA 95131
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 CD95lowCD28high
7
integrinint (CD4+) or
CD95lowCD28intCD11alow
(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-
production capability, and specific
responses to RM CMV; and 4) demonstrated low in vivo proliferative
activity. CD4+ and CD8+ memory subsets were
CD95high, but otherwise phenotypically heterogeneous and
included all IFN- production, RM CMV-specific responses, effector
site T cells, and demonstrated high in vivo proliferative activity
(
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.
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