Functional signatures of protective antiviral T‐cell immunity in human virus infections

Abstract

The most common human viruses have different abilities to establish persistent chronic infection. Virus-specific T-cell responses are critical in the control of virus replication and in the prevention of disease in chronic infection. A large number of phenotypic markers and a series of functions have been used to characterize virus-specific CD4+ and CD8+ T-cell responses, and these studies have shown great phenotypic and functional heterogeneity of the T-cell responses against different viruses. The heterogeneity of the T-cell response has been proposed to be specific to each virus. However, over the past 2 years, several studies have provided evidence that the phenotypic and functional heterogeneity of CD4+ and CD8+ T-cell responses is predominantly regulated by the levels of antigen load. The levels of antigen load modulate the phenotypic and functional patterns of the T-cell response within the same virus infection. Furthermore, the functional characterization of virus-specific CD4+ and CD8+ T-cell responses has identified signatures of protective antiviral immunity. Polyfunctional, i.e. interleukin-2 and interferon-gamma (IFN-gamma) secretion and proliferation, and not monofunctional, i.e. IFN-gamma secretion, CD4+ and CD8+ T-cell responses represent correlates of protective antiviral immunity in chronic virus infections.

T cell differentiation in chronic infection and cancer: functional adaptation or exhaustion?

“…Such acute infections trigger the generation of large numbers of short-lived effector T-cells and the formation of memory T-cells [1][2][3][4][5][6][7][8] . Following such infections, T-cells typically co-express multiple cytokines (TNF, IFN IL-2) and cytotoxic effector molecules -a phenotype often referred to as polyfunctional 9 . A different outcome arises when infections become chronic and when viruses persist at high levels over long periods as in Human-Immunodeficiency-Virus (HIV) or Human-Hepatitis-C Virus (HCV) infections.…”

“…A different outcome arises when infections become chronic and when viruses persist at high levels over long periods as in Human-Immunodeficiency-Virus (HIV) or Human-Hepatitis-C Virus (HCV) infections. Such conditions induce T-cells lacking the typical polyfunctional phenotype and T-cells retain the expression of inhibitory receptors including PD-1, Lag-3, Tim-3, and CD160 [9][10][11][12][13][14][15][16][17] . Very similar phenotypes can be observed, when T-cells are long-term exposed to tumor-antigen [18][19][20] .…”

Polyfunctional T cells in human tuberculosis

“…Studies of chronic viral infections such as cytomegalovirus, Epstein-Barr Virus, and others have highlighted the phenotypic and functional heterogeneity of the antigenspecific CD4 1 and CD8 1 T-cell responses, and provided evidence that they are dependent on, and modulated by, antigen concentration [6]. Overall it has been shown that polyfunctional T cells that secrete multiple cytokines and are able to proliferate are more likely than single cytokine secretors to represent correlates of protective antiviral immunity in chronic infections (when antigen load is low), while single IFN-g-secreting CD4 1 and CD8 1 T cells are characteristic of acute infections (when antigen load is high) [7]. If chronic infection ensues after failure of complete immune control, the balance of responding T cells tends to shift towards the single IFN-g-secreting phenotype.…”

Reflections on the immunology of tuberculosis: will we ever unravel the skein?

“…Central memory T-cells have high proliferative activity and produce IL-2, whereas effector memory T-cells produce bothIL-2 and IFN-γ. Circulating effector memory T-cells indicates that an antigen-specific response persists, whereas circulating central memory T-cells indicate that infection has been controlled [28]. …”