Divergent Generation of Heterogeneous Memory CD4 T Cells

Abstract

Mechanisms for the generation of memory CD4 T cells and their delineation into diverse subsets remain largely unknown. In this study, we demonstrate in two Ag systems, divergent generation of heterogeneous memory CD4 T cells from activated precursors in distinct differentiation stages. Specifically, we show that influenza hemagglutinin- and OVA-specific CD4 T cells activated for 1, 2, and 3 days, respectively, exhibit gradations of differentiation by cell surface phenotype, IFN-γ production, and proliferation, yet all serve as direct precursors for functional memory CD4 T cells when transferred in vivo into Ag-free mouse hosts. Using a conversion assay to track the immediate fate of activated precursors in vivo, we show that day 1- to 3-activated cells all rapidly convert from an activated phenotype (CD25highIL-7RlowCD44high) to a resting memory phenotype (IL-7RhighCD25lowCD44high) 1 day after antigenic withdrawal. Paradoxically, stable memory subset delineation from undifferentiated (day 1- to 2-activated) precursors was predominantly an effector memory (CD62Llow) profile, with an increased proportion of central memory (CD62Lhigh) T cells arising from more differentiated (day 3-activated) precursors. Our findings support a divergent model for generation of memory CD4 T cells directly from activated precursors in multiple differentiation states, with subset heterogeneity maximized by increased activation and differentiation during priming.

IL-7 receptor blockade reverses autoimmune diabetes by promoting inhibition of effector/memory T cells

“…Because of the general decrease in CD4 + T cells (Fig. S1C) (18)(19)(20). To directly rule out that IL-7Rα blockade led to selective deletion of CD44 high IL-7Rα high memory T cells, we stained CD4 + T-cell populations from isotype and anti-IL-7Rα-treated mice with fluorescently labeled anti-rat Ig secondary antibodies to detect cells whose surface was coated with anti-IL-7Rα antibodies in vivo.…”

TLR2 Engagement on Dendritic Cells Promotes High Frequency Effector and Memory CD4 T Cell Responses

“…The resultant CD4 T cells were further fractionated into CD44 low , naive CD4 T cells by negative selection using the autoMACS (Miltenyi Biotec) and anti-CD44-FITC and anti-FITC magnetic microbeads as previously described (40), yielding 98% purity. Naive CD4 T cells were labeled with CFSE (Invitrogen) and adoptively transferred (200,000 cells/mouse) into congenic BALB/c (Thy1.1) hosts as described elsewhere (40). One day after transfer, mice were primed i.p.…”

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

“…More complex and controversial are the pathways for generating and maintaining T CM and T EM , and the specific contributions of these subsets to long-term protection (23)(24)(25)(26)(27)(28)(29)(30)(31). T EM have been described as having higher rates of cell division (32) and cell death (33)(34)(35), leading to the proposition that the T EM are a short-lived population.…”