Characterization of subsets of CD4+ memory T cells reveals early branched pathways of T cell differentiation in humans.
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.
Song
Kaimei
K
Inflammation Biology Section, Laboratory of Molecular Immunology and Sections of Human Immunology and ImmunoTechnology, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Rabin
Ronald L
RL
Hill
Brenna J
BJ
De Rosa
Stephen C
SC
Perfetto
Stephen P
SP
Zhang
Hongwei H
HH
Foley
John F
JF
Reiner
Jeffrey S
JS
Liu
Jie
J
Mattapallil
Joseph J
JJ
Douek
Daniel C
DC
Roederer
Mario
M
Farber
Joshua M
JM
D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D002454:Cell Differentiation / Q000276:immunology*; D002478:Cells, Cultured; D005434:Flow Cytometry; D015870:Gene Expression / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D017403:In Situ Hybridization; D008024:Ligands; D014066:Palatine Tonsil / Q000166:cytology; D054398:Receptors, CCR4; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000166:cytology*; D013755:Tetradecanoylphorbol Acetate
C515354:CCR4 protein, human; C515187:CXCR3 protein, human; D008024:Ligands; D054398:Receptors, CCR4; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D013755:Tetradecanoylphorbol Acetate