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

Abstract

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 naïve 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 ؉ ''naïve'' populations contain Th1 and Th2 cells, respectively, demonstrating that Th1͞Th2 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 naïve 3 CD45RO ؉ noneffector͞central memory 3 effector͞effector memory cells. Rather, developmental pathways branch early on to yield effector͞memory populations that are highly heterogeneous and multifunctional and have the potential to become stable resting cells.chemokines ͉ immunologic memory ͉ Th1͞Th2 cells U nderstanding how immunological memory develops and is sustained is a focus of ongoing research, in part because successful vaccination requires the production of long-lived memory (1, 2). Such an understanding depends on identifying subsets of memory cells, characterizing their functions, and mapping the pathways through which they are generated. As the molecular determinants of lymphocyte trafficking have been defined, the association between T cells' migratory capacities and their functions has been used to characterize T cell subsets. It was reported, for example, that expression of the chemokine receptor CCR7 identifies a subset of memory cells, so-called central memory (T CM ) cells, that coexpress L-selectin (CD62L) and, in addition to being able to enter lymphoid organs, are functionally distinct from the CCR7 Ϫ subset, so-called effector memory (T EM ) cells (3). The key findings were that T EM but not T CM cells could produce effector cytokines and that T CM cells could serve, in vitro, as precursors for effector cells. Sallusto et al. (4) have hypothesized a linear pathway of T cell differentiation of naïve 3 CD45RO ϩ ͞CD45RA Ϫ noneffector͞T CM 3 effector and T EM cells, driven by the strength of the activating signals. In this model, T CM cells provide ''reactive memory'' and serve as a long-lived pool of precursors for additional memory and effector cells.Our studies of how patterns of chemokine-recep...

CCR2 Identifies a Stable Population of Human Effector Memory CD4+ T Cells Equipped for Rapid Recall Response

“…In addition to loss of expression of CD62L and CCR7, loss of CD27 and CD28 (34,45,46) (Table I). A number of biochemical and functional features distinguish effector/memory versus naive cells (49,50) (44,(50)(51)(52). As shown in Fig.…”

“…As compared with CD62L + cells, CD62L 2 cells have shorter telomeres (43) and fewer TREC (44). The patterns of expression of CCR5, CCR2, and CD62L (Fig.…”

Differentiation of Human T Cells Alters Their Repertoire of G Protein α-Subunits

“…In later experiments (indicated in the legends to Figs. 2, 3, and 8), CD4 ϩ and CD8 ϩ T cell subsets were first purified by negative selection with either the RosetteSep CD4 ϩ T cell or CD8 ϩ T cell enrichment mixtures (StemCell Technologies, Vancouver, British Columbia, Canada) as described previously (17), and naive and effector/memory subsets were purified by sorting using a FACSAria flow cytometer (BD Biosciences) after staining with the following antibodies obtained from BD Biosciences: FITC-conjugated anti-CD8, phycoerythrin-conjugated anti-CD62L, phycoerythrin-Cy5-conjugated anti-CD3, allophycocyaninconjugated anti-CD45RO, and allophycocyanin-Cy7-conjugated anti-CD4 as described previously (18). It is noteworthy that published experiments have demonstrated the cleavage of CD62L from the surface of lymphocytes through the activity of a zinc metalloproteinase (19,20).…”

CD4 + Memory Stem Cells Are Infected by HIV-1 in a Manner Regulated in Part by SAMHD1 Expression

“…Over the past decade, it has become apparent that the naïve CD4 ϩ T cell subset is not a homogeneous cell population but rather contains several distinct subsets, including CD31 ϩ recent thymic emigrants (26,27), CD44 very low "supernaïve" CD4 ϩ T cells (28), CXCR3 ϩ or CXCR4 ϩ early-memory cells (29), and a recently described subset of CD95…”