Abstract
SummaryCD4+ T cells develop distinct and often contrasting helper, regulatory, or cytotoxic activities. Typically a property of CD8+ T cells, granzyme-mediated cytotoxic T cell (CTL) potential is also exerted by CD4+ T cells. However, the conditions that induce CD4+ CTLs are not entirely understood. Using single-cell transcriptional profiling, we uncover a unique signature of Granzyme B (GzmB)+ CD4+ CTLs, which distinguishes them from other CD4+ T helper (Th) cells, including Th1 cells, and strongly contrasts with the follicular helper T (Tfh) cell signature. The balance between CD4+ CTL and Tfh differentiation heavily depends on the class of infecting virus and is jointly regulated by the Tfh-related transcription factors Bcl6 and Tcf7 (encoding TCF-1) and by the expression of the inhibitory receptors PD-1 and LAG3. This unique profile of CD4+ CTLs offers targets for their study, and its antagonism by the Tfh program separates CD4+ T cells with either helper or killer functions.
Highlights
CD4+ TCRab T cells centrally orchestrate multiple arms of innate and adaptive immunity using distinct and, often, opposing effector and regulatory functions through the differentiation of distinguishable functional CD4+ T cell subsets (O’Shea and Paul, 2010; Swain et al, 2012; Zhu et al, 2010)
CD4+ CTL Development Depends on Infecting Virus We have previously described an adoptive transfer system that allows the study of the CD4+ T cell response to the dominant H2-Ab-restricted env122–141 epitope within the Friend murine leukemia virus (F-MLV) gp70 glycoprotein (Merkenschlager et al, 2016; Thorborn et al, 2014)
Small numbers of allotypically marked EF4.1 TCRb-transgenic CD4+ T cells were transferred into wild-type (WT) C57BL/6 (B6) recipients and primed either by infection with Friend virus (FV) or by immunization with a human Adenovirus 5 (Ad5)-based vector expressing F-MLV gp70 (Ad5.pIX-gp70) (Bayer et al, 2010)
Summary
Julia Merkenschlager, ..., Mirko Trilling, Wibke Bayer, George Kassiotis. In Brief ‘‘Helper’’ CD4 T cells can exhibit granzyme-mediated cytotoxicity. Donnarumma et al investigate the conditions that induce CD4 CTLs and describe the dominant effect of the class of infecting virus. They uncover a unique transcriptional signature of CD4 CTLs and its multi-layered control. Highlights d Adenoviruses prime CD4 T cells with CTL potential, but retroviruses do not d CD4 CTLs are transcriptionally distinguishable from other Th cells d The CD4 CTL program is the direct opposite of the Tfh program d CD4 CTLs are restrained by the TCF-1-Bcl nexus and by PD-1 and LAG3. Donnarumma et al, 2016, Cell Reports 17, 1571–1583 November 1, 2016 a 2016 The Author(s).
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