Single-cell RNA sequencing unveils an IL-10-producing helper subset that sustains humoral immunity during persistent infection

Abstract

During chronic viral infection, the inflammatory function of CD4 T-cells becomes gradually attenuated. Concurrently, Th1 cells progressively acquire the capacity to secrete the cytokine IL-10, a potent suppressor of antiviral T cell responses. To determine the transcriptional changes that underlie this adaption process, we applied a single-cell RNA-sequencing approach and assessed the heterogeneity of IL-10-expressing CD4 T-cells during chronic infection. Here we show an IL-10-producing population with a robust Tfh-signature. Using IL-10 and IL-21 double-reporter mice, we further demonstrate that IL-10+IL-21+co-producing Tfh cells arise predominantly during chronic but not acute LCMV infection. Importantly, depletion of IL-10+IL-21+co-producing CD4 T-cells or deletion of Il10 specifically in Tfh cells results in impaired humoral immunity and viral control. Mechanistically, B cell-intrinsic IL-10 signaling is required for sustaining germinal center reactions. Thus, our findings elucidate a critical role for Tfh-derived IL-10 in promoting humoral immunity during persistent viral infection.

Chronic Viral Infection Promotes Efficient Germinal Center B Cell Responses

“…Interestingly, the CD4 differentiation profiles that predominate under these respective conditions are predicted to support a shift from cellular to humoral immune defense: with progression to chronicity T helper 1 (Th1) responses become exhausted (Brooks et al, 2005;Kaufmann et al, 2007;Oxenius et al, 1998), similar to CD8 + T cells, whereas T follicular helper (Tfh) cells start to dominate the CD4 T cell response (Fahey et al, 2011;Feng et al, 2012;Lindqvist et al, 2012). Chronic infection also favors the emergence of Tfh cells with distinct functional profiles, such as the ability to co-produce interleukin (IL)-10 and IL-21 (Xin et al, 2018). Accordingly, potent Tfh responses represent an essential component of efficient GC reactions in the chronic infection context (Greczmiel et al, 2017;Harker et al, 2011;Xin et al, 2018).…”

Follicular regulatory T cells: a novel target for immunotherapy?

“…IL‐10, however, has aroused controversies in Tfr‐cell effector function. Tfh cells also secrete IL‐10–like Tfr cells, and IL‐10 + Tfh cells can help GC responses in mice, as specific deletion of IL‐10 in Tfh cells leads to impaired humoral immunity during chronic viral infection . In addition, Tfr cells suppress IL‐10 production by Tfh cells and in the coculture supernatants .…”

“…Tfh cells also secrete IL-10-like Tfr cells, and IL-10 + Tfh cells can help GC responses in mice, as specific deletion of IL-10 in Tfh cells leads to impaired humoral immunity during chronic viral infection. 55 In addition, Tfr cells suppress IL-10 production by Tfh cells and in the coculture supernatants. 16 Consistent with its suppressive function, IL-10 inhibition impedes GC responses and humoral immunity.…”

TFH cells in bystander and cognate interactions with B cells

“…By the time activated CD4 + T cells become fully competent effector cells, they are generally thought of as functionally polarized in one or another lineage, although some clone members may maintain a level of plasticity, remain responsive to distinct differentiation cues, and therefore are able to trans-differentiate in environment conducive to choices of other lineages. In addition to IL-21, T FH cells have been found in various models of infection and immunization to produce IFNγ, 6 IL-4, 7-9 IL-17, 10 IL-9, 11 and IL-10, 12 all of which can modulate certain but not all aspects of GC biology. 4 Th1, Th2, and Th17 cells all have signature cytokines that are responsible for their respective lineage-defining functions, and expression of those cytokines are transcriptionally and epigenetically controlled by their respective lineage-specifying master transcription regulators.…”

“…5 However, the main functions of T FH cells are not mediated by a single cytokine or a combination of cytokines that are coordinately regulated by BCL-6. In addition to IL-21, T FH cells have been found in various models of infection and immunization to produce IFNγ, 6 IL-4, 7-9 IL-17, 10 IL-9, 11 and IL-10, 12 all of which can modulate certain but not all aspects of GC biology. Some of these cytokines may even have opposite biological effects on GC B cells.…”