Scientific Publications by FDA Staff

Proc Natl Acad Sci U S A 2005 May 31;102(22):7916-21

Characterization of subsets of CD4+ memory T cells reveals early branched pathways of T cell differentiation in humans.

Song K, Rabin RL, Hill BJ, De Rosa SC, Perfetto SP, Zhang HH, Foley JF, Reiner JS, Liu J, Mattapallil JJ, Douek DC, Roederer M, Farber JM

Farber JM, NIH, Inflammat Biol Sect, Lab Mol Immunol, NIAID,Vaccine Res Ctr, 10 Ctr Dr,Room 11N-107, Bethesda, MD 20892 USA NIH, Inflammat Biol Sect, Lab Mol Immunol, NIAID,Vaccine Res Ctr, Bethesda, MD 20892 USA NIH, Sect Human Immunol, Vaccine Res Ctr, Bethesda, MD 20892 USA NIH, Sect ImmunoTechnol, Vaccine Res Ctr, Bethesda, MD 20892 USA US FDA, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA

The pathways for differentiation of human CD4(+) T cells into functionally distinct subsets of memory cells in vivo are unknown. The identification of these subsets and pathways has clear implications for the design of vaccines and immune-targeted therapies. Here, we show that populations of apparently naive CD4(+) T cells express the chemokine receptors CXCR3 or CCR4 and demonstrate patterns of gene expression and functional responses characteristic of memory cells. The proliferation history and T cell receptor repertoire of these chemokine-receptor(+) cells suggest that they are very early memory CD4(+) T cells that have "rested down" before acquiring the phenotypes described for "central" or "effector" memory T cells. In addition, the chemokine-receptor(+) "naive" populations contain Th1 and Th2 cells, respectively, demonstrating that Th1/Th2 differentiation can occur very early in vivo in the absence of markers conventionally associated with memory cells. We localized ligands for CXCR3 and CCR4 to separate foci in T cell zones of tonsil, suggesting that the chemokine-receptor(+) subsets may be recruited and contribute to segregated, polarized microenvironments within lymphoid organs. Importantly, our data suggest that CD4(+) T cells do not differentiate according to a simple schema from naive --> CD45RO(+) noneffector/central memory --> effector/effector memory cells. Rather, developmental pathways branch early on to yield effector/memory populations that are highly heterogeneous and multifunctional and have the potential to become stable resting cells.