Cytokine-Mediated Regulation of CD8 T-Cell Responses During Acute and Chronic Viral Infection

Abstract

The common γ-chain cytokines, interleukin (IL)-2, IL-7, and IL-15, regulate critical aspects of antiviral CD8 T-cell responses. During acute infections, IL-2 controls expansion and differentiation of antiviral CD8 T cells, whereas IL-7 and IL-15 are key cytokines to maintain memory CD8 T cells long term in an antigen-independent manner. On the other hand, during chronic infections, in which T-cell exhaustion is established, precise roles of these cytokines in regulation of antiviral CD8 T-cell responses are not well defined. Nonetheless, administration of IL-2, IL-7, or IL-15 can increase function of exhausted CD8 T cells, and thus can be an attractive therapeutic approach. A new subset of stem-cell-like CD8 T cells, which provides a proliferative burst after programmed cell death (PD)-1 therapy, has been recently described during chronic viral infection. Further understanding of cytokine-mediated regulation of this CD8 T-cell subset will improve cytokine therapies to treat chronic infections and cancer in combination with immune checkpoint inhibitors.

Figure 1.

Cytokines (interleukin [IL]-2, IL-7, and IL-15) and their receptors. Each cytokine-binding homology region (CHR), composed of tandem fibronectin type III domains, contains three yellow lines that represent conserved disulfides and a WSXWS motif. γc, Common γ-chain.

Figure 2.

Cytokine-mediated control of antiviral CD8 T-cell responses and their differentiation from naïve to effector to memory cells during acute infections. The black solid line indicates the dynamics of the number of antiviral CD8 T cells. The red solid line indicates the dynamics of the viral load. The dotted line indicates the limit of detection. Levels of CD127 expression on antiviral CD8 T cells at different stages of T-cell differentiation are shown. IL, Interleukin.

Figure 3.

Composition of antiviral CD8 T cells during chronic infections and potential regulation by cytokines. (A) Two programmed cell death (PD)-1-expressing CD8 T-cell subsets in T-cell exhaustion and their biological characteristics/functions. Two (stem-cell-like and terminally differentiated) CD8 T-cell subsets are distinct from each other in terms of generation/maintenance, proliferative capacity, molecular signature, and location. (B) Potential regulation of antiviral CD8 T cells by cytokines during chronic infections. Cytokines may regulate two (stem-cell-like and terminally differentiated) CD8 T-cell subsets at four levels: (1) self-renewal of stem-cell-like CD8 T cells, (2) proliferation/differentiation of stem-cell-like CD8 T cells, (3) migration of terminally differentiated CD8 T cells into major sites of infection, and (4) effector function of terminally differentiated CD8 T cells. ICOS, Inducible T-cell costimulator; TCF-1, T-cell factor 1; Id3, inhibitor of DNA binding 3; Bcl-6, B-cell leukemia/lymphoma 6; Tim-3, T-cell immunoglobulin and mucin-domain containing-3; Blimp-1, B-lymphocyte-induced maturation protein; Id2, inhibitor of DNA binding 2; MP, memory precursor; TE, terminal effector; Tfh, T follicular helper; Th1, T helper type I.