Regulation of CD4 T cells and their effects on immunopathological inflammation following viral infection

Abstract

CD4 T cells help immune responses, but knowledge of how memory CD4 T cells are regulated and how they regulate adaptive immune responses and induce immunopathology is limited. Using adoptive transfer of virus-specific CD4 T cells, we show that naive CD4 T cells undergo substantial expansion following infection, but can induce lethal T helper type 1-driven inflammation. In contrast, memory CD4 T cells exhibit a biased proliferation of T follicular helper cell subsets and were able to improve adaptive immune responses in the context of minimal tissue damage. Our analyses revealed that type I interferon regulates the expansion of primary CD4 T cells, but does not seem to play a critical role in regulating the expansion of secondary CD4 T cells. Strikingly, blockade of type I interferon abrogated lethal inflammation by primary CD4 T cells following viral infection, despite that this treatment increased the numbers of primary CD4 T-cell responses. Altogether, these data demonstrate important aspects of how primary and secondary CD4 T cells are regulated in vivo, and how they contribute to immune protection and immunopathology. These findings are important for rational vaccine design and for improving adoptive T-cell therapies against persistent antigens.

Interrogating Adaptive Immunity Using LCMV

“…Therefore, it is advisable to transfer between 10 4 and 10 5 SMARTA cells to be able to visualize them after viral infection. A critical consideration is that injection of >10 6 naïve SMARTA cells can result in immunopathology after chronic LCMV Cl-13 challenge (Bhattacharyya et al, 2017a (Fallet et al, 2016;Moseman, Wu, de la Torre, Schwartzberg, & McGavern, 2016;Sammicheli et al, 2016). Therefore, it is advisable to adoptively transfer high numbers (>5 × 10 6 ) of KL25 B cells to allow their detection in vivo.…”

“…PD-1-based immunotherapy for the treatment of chronic infection was first shown in the chronic LCMV Cl-13 model (Barber et al, 2006), and was then shown to also be effective in the SIV model in macaques (Velu et al, 2009). Many studies on immune regulation have utilized the LCMV system (Bhattacharyya et al, 2017b;Bhattacharyya & Penaloza-MacMaster, 2017, 2018Im et al, 2016;Kamphorst et al, 2017;Penaloza-MacMaster et al, 2011;Penaloza-MacMaster, Kamphorst et al, 2014;Penaloza-MacMaster, Masopust, & Ahmed, 2009;Penaloza-MacMaster, Provine, Blass, & Barouch, 2015;Penaloza-MacMaster, Teigler et al, 2014;Vezys et al, 2011;Wang et al, 2019;West et al, 2013;West et al, 2011).…”

“…For example, we previously interrogated whether memory CD4 T cells would exhibit enhanced expansion relative to naïve CD4 T cells. To answer this simple question, we performed the following experiment from our prior publication (Bhattacharyya et al, 2017a).…”

“…Sample data shown in Figure 9 were obtained from our prior publication (Bhattacharyya et al, 2017a). Paradoxically, memory SMARTA cells expand less than naïve SMARTA cells when co-transferred at equal numbers into the same host.…”

“…One could also transfer memory and naïve SMARTA cells separately into different mice, and then compare immune responses and protection following LCMV Cl-13 challenge. In this context, memory CD4 T cells conferred improved help to adaptive immune responses, relative to naïve CD4 T cells (Bhattacharyya et al, 2017a).…”