Differential Expression of Ly6C and T-bet Distinguish Effector and Memory Th1 CD4 + Cell Properties during Viral Infection

Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
Immunity (Impact Factor: 21.56). 10/2011; 35(4):633-46. DOI: 10.1016/j.immuni.2011.08.016
Source: PubMed


CD4(+) T cells differentiate into multiple effector types, but it is unclear how they form memory T cells during infection in vivo. Profiling virus-specific CD4(+) T cells revealed that effector cells with T helper 1 (Th1) or T follicular helper (Tfh) cell characteristics differentiated into memory cells, although expression of Tfh cell markers declined over time. In contrast to virus-specific effector CD8(+) T cells, increased IL-7R expression was not a reliable marker of CD4(+) memory precursor cells. However, decreased Ly6C and T-bet (Tbx21) expression distinguished a subset of Th1 cells that displayed greater longevity and proliferative responses to secondary infection. Moreover, the gene expression profile of Ly6C(lo)T-bet(int) Th1 effector cells was virtually identical to mature memory CD4(+) T cells, indicating early maturation of memory CD4(+) T cell features in this subset during acute viral infection. This study provides a framework for memory CD4(+) T cell development after acute viral infection.

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    • "Therefore, we performed RNA-sequencing (RNA-seq) on sorted polyclonal CD4 + CD44 + T cells from WT and STAT3-deficient CD4 + T cells, again by using Ly6c and PSGL-1 expression to distinguish the three effector populations, with further gating on the CXCR5 hi group within the Ly6c lo PSGL-1 lo subset to distinguish Tfh cells (Figure 1A; Figure S1A). We used a multidimensional scaling plot to relate the similarities and differences among the populations relative to one another (Figure S3A), finding that Stat3 fl/fl cre-negative WT Tfh cells (Ly6c lo PSGL-1 lo CXCR5 hi ) had vastly different gene expression than either their Th1 Ly6c lo PSGL-1 hi or Th1 Ly6c hi PSGL-1 hi counterparts, validating their separation by surface marker expression (Marshall et al., 2011). In addition, we used unbiased K-means clustering to determine how global STAT3- deficient Tfh cell gene expression compares to the three WT populations (Figure 4A; Figure S3B). "
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    ABSTRACT: Follicular helper T (Tfh) cells are required for the establishment of T-dependent B cell memory and high affinity antibody-secreting cells. We have revealed herein opposing roles for signal transducer and activator of transcription 3 (STAT3) and type I interferon (IFN) signaling in the differentiation of Tfh cells following viral infection. STAT3-deficient CD4(+) T cells had a profound defect in Tfh cell differentiation, accompanied by decreased germinal center (GC) B cells and antigen-specific antibody production during acute infection with lymphocytic choriomeningitis virus. STAT3-deficient Tfh cells had strikingly increased expression of a number of IFN-inducible genes, in addition to enhanced T-bet synthesis, thus adopting a T helper 1 (Th1) cell-like effector phenotype. Conversely, IFN-αβ receptor blockade restored Tfh and GC B cell phenotypes in mice containing STAT3-deficient CD4(+) T cells. These data suggest mutually repressive roles for STAT3 and type I IFN signaling pathways in the differentiation of Tfh cells following viral infection.
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    • "Previous studies have also demonstrated the maintenance of the CD62Llo phenotype on endogenous memory CD4 T cells, although at least two studies have also demonstrated memory CD4 T cells that can reacquire high levels of CD62L [9]–[11], [36], [37]. However, in both of these latter studies CD62L expression was examined on transgenic memory CD4 T cells [36], [37]. As a result, the utility of CD62L in classifying CD4 memory T cells remains controversial, and a few recently published studies have utilized other markers, such as Ly6C, PSGL-1, T-bet and Blimp-1 to characterize memory CD4 T cells [36], [38]. "
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    • "The proliferating T cells then differentiate into effector cells that enhance the microbicidal activities of macrophages or help B cells secrete antibodies (Zhu et al., 2010). This process has been studied during acute infections with an attenuated strain of the Listeria monocytogenes (Lm) bacterium or lymphocytic choriomeningitis virus (LCMV) (Marshall et al., 2011; Pepper et al., 2011). Early after infection, naive CD4 + T cells with microbe p:MHCII-specific TCRs proliferate and differentiate into Th1 effector cells, which produce the macrophageactivating cytokine IFN-g, or into one of two types of follicular helper cells—Tfh cells that augment B cell activation at the border between the T cell areas and follicles or GC-Tfh cells that drive affinity maturation in germinal centers (Choi et al., 2011; Crotty, 2011; Lee et al., 2011; Pepper et al., 2011). "
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