Virus-specific CD4 and CD8 T cell responses in the absence of Th1-associated transcription factors

Abstract

Effector and memory CD4 and CD8 T cell responses are critical for the control of many intracellular pathogens. The development of these populations is governed by transcription factors that molecularly control their differentiation, function, and maintenance. Two transcription factors known to be involved in these processes are Tbet and STAT4. Although Tbet has been shown to regulate CD8 T cell fate decisions and effector CD4 T cell choices, the contribution of STAT4 is less well understood. To address this, we examined the impact of STAT4 on T cell responses in the presence or absence of Tbet, following LCMV infection by using mice lacking Tbet, STAT4, or both transcription factors. STAT4 was not required for Tbet or Eomes expression; however, virus-specific effector CD8 T cells are skewed toward a memory-precursor phenotype in the absence of STAT4. This altered proportion of memory precursors did not result in an increase in memory CD8 T cells after the resolution of the infection. We also demonstrate that virus-specific effector and memory CD4 T cells formed independently of Tbet and STAT4, although a slight reduction in the number of antigen-specific CD4 T cells was apparent in mice lacking both transcription factors. Collectively, we have discovered distinct roles for Tbet and STAT4 in shaping the phenotype and function of virus-specific T cell responses.

Memory CD4+ T Cells in Immunity and Autoimmune Diseases

“…Shown in Figure 2 is the integration of TCR signaling-and inflammation-dependent factors influencing memory T cell development. compared with mice lacking either one of these transcription factors (STAT4 or T-bet) [61]. These data suggest that early activation of STAT4 and T-bet may not be required for development of CD4 + T cell memory; however, their expression may affect the quality of memory responses during recall and the type (subset) of memory generated.…”

“…Similarly, IL-12 induces the expression of T-bet in a STAT4-dependent manner in CD4 + T cells [59], and IL-12 promotes development of hepatitis B virus (HBV)-specific CD8 + T EM cells [60]. Along these lines, although no data exists for the role of IL-12 in development of CD4 + memory T cells, mice lacking both STAT4 and T-bet have marginally reduced virus-specific CD4 + memory T cell frequencies as compared with mice lacking either one of these transcription factors (STAT4 or T-bet) [61]. These data suggest that early activation of STAT4 and T-bet may not be required for development of CD4 + T cell memory; however, their expression may affect the quality of memory responses during recall and the type (subset) of memory generated.…”

Functional delineation of tissue-resident CD8+T cell heterogeneity during infection and cancer

“…This diversity in circulating memory T cell states endows the immune response with flexibility, allowing both rapid and sustained responses as well as the generation of secondary memory populations that retain these characteristics. Differentiation and maintenance of circulating memory subsets are also dynamically controlled by a compendium of transcription factors, including: Id2 (Cannarile et al, 2006;Knell et al, 2013;Masson et al, 2013), T-bet (Joshi et al, 2007), Blimp1 (Kallies et al, 2009;Rutishauser et al, 2009) Zeb2 (Dominguez et al, 2015;Omilusik et al, 2015), and STAT4 (Mollo et al, 2014) that are critical for TEM, and Id3 (Ji et al, 2011;Yang et al, 2011), Eomes (Banerjee et al, 2010;Pearce et al, 2003), Bcl6 (Ichii et al, 2002), Foxo1 (Hess Michelini et al, 2013;Rao et al, 2012), Tcf1 (Jeannet et al, 2010;Zhou et al, 2010), Zeb1 (Guan et al, 2018), Bach2 (Roychoudhuri et al, 2016), and STAT3 (Cui et al, 2011) that support TCM differentiation. TRM heterogeneity has been alluded to in multiple non-lymphoid sites and infection models (Bergsbaken and Bevan, 2015;Bergsbaken et al, 2017;Boddupalli et al, 2016;Harrison et al, 2019;Kumar et al, 2018;Masopust and Soerens, 2019), and differing levels of CD69 and CD103 have been useful in studying TRM maturation.…”

Human Memory, but Not Naive, CD4+ T Cells Expressing Transcription Factor T-bet Might Drive Rapid Cytokine Production

“…Studies in mice showed that following LCMV infection, virus-specific effector and memory CD4 ϩ T cells formed independently of T-bet and STAT-4 (12). The functions of transcription factors in human memory CD4 ϩ T * This study was supported by grants from Guangdong Recruitment Program cells remain largely unknown.…”