Maintenance, Loss, and Resurgence of T Cell Responses During Acute, Protracted, and Chronic Viral Infections

Abstract

The acute phase of many viral infections is associated with the induction of a pronounced CD8 T cell response which plays a principle role in clearing the infection. By contrast, certain infections are not as readily controlled. In this study, we have used the well-defined system of lymphocytic choriomeningitis virus (LCMV) infection of mice to determine quantitative and qualitative changes in virus-specific CD8 T cell responses that rapidly resolve acute infections, more slowly control protracted infections, or fail to clear chronic infections. Acute LCMV infection elicits potent, functional, multi-epitope-specific CD8 T cell responses. Virus-specific CD8 T cells also expand, albeit to a lesser extent, during protracted LCMV infection. Under these conditions, there is a progressive diminution in the capacity to produce IL-2, TNF-α, and IFN-γ. Changes in cytotoxic activities are also detectable but differ depending upon the specificity of the responding cells. As the infection is slowly resolved, a resurgence of cytokine production by virus-specific CD8 T cells is observed. CD4-deficient mice cannot control infection with certain strains of LCMV, but do mount multi-epitope-specific CD8 T cell responses that also lose effector capabilities; however, they are not maintained indefinitely in an unresponsive state as these cells become deleted over time. Overall, our findings suggest that constant high viral loads result in the progressive diminution of T cell effector functions and subsequent physical loss of the responding cells, whereas if the viral load is brought under control a partial restoration of CD8 T cell functions can occur.

Single-Epitope DNA Vaccination Prevents Exhaustion and Facilitates a Broad Antiviral CD8+ T Cell Response during Chronic Viral Infection

“…The above findings are consistent with the hypothesis that the generation of a potent and broadly reactive CD8 ϩ T cell population is decided by a delicate balance between the initial CD8 ϩ T cell response and the viral load (42,54). In control mice infected with LCMV clone 13 (H-2 b and H-2 d ), the absence of primed LCMV-specific, CD8 ϩ T cells results in a high viral load, which subsequently leads to a progressive failure of the antiviral CD8 ϩ T cell response.…”

“…Notably, NP396 -404-specific, CD8 ϩ T cells lost effector functions earlier and more completely than did gp33-41 and gp276 -286-specific cells in control mice during chronic conditions. This has been observed previously (28,54) and probably explains why it was more difficult to maintain the NP396 -404-specific T cell population in gp33-vaccinated mice than to maintain the gp33-41-specific T cell population in NP396-vaccinated mice.…”

Differential role of IL‐2R signaling for CD8+ T cell responses in acute and chronic viral infections

“…The reason(s) for this strict dependence of CD8 + T cell maintenance during chronic infection on IL-2R signaling remains to be determined, but it could relate to the very high turnover of virus-specific CD8 + T cells during chronic infection due to continued antigen encounter ( [40,54] and Agnellini et al, unpublished observations), which might be dependent on IL-2R signaling. The source of the relevant IL-2 remains to be determined; however, it is rather unlikely that CD4 + or CD8 + T cells are the major source, since they are generally unable to produce measurable amounts of IL-2 during chronic viral infection ( [30,31,55] and Agnellini et al, unpublished observations). It is conceivable, however, that some IL-2 production by LCMV-specific T cells might occur during the very early phases of the chronic infection, which might allow the differentiation of CD8 + T cells that can be maintained during chronic infection.…”

“…6B). Dysfunction of virusspecific CD8 + T cells with respect to cytokine production but to a lesser extent with respect to degranulation seems to be common during high-level chronic viral infection ( [29][30][31][32][33][34][35][36][37] and Agnellini et al, unpublished observations).…”

Antigen amount dictates CD8+T‐cell exhaustion during chronic viral infection irrespective of the type of antigen presenting cell

“…During highly replicative chronic viral infections such as HIV-1, hepatitis B or hepatitis C virus infection in humans, or lymphocytic choriomeningitis virus (LCMV) in mice, virus-specific CD8 + T cells initially expand and acquire effector functions early after infection but then gradually lose these functions [1][2][3][4][5][6][7][8] in a hier-archical manner: first the ability to produce IL-2 and to proliferate, then TNF-α secretion and last IFN-γ production become impaired [9][10][11][12]. This T-cell dysfunction, also termed CD8 + T-cell exhaustion, is well studied after infection of mice with a high dose of LCMV clone 13 or LCMV-Docile [13].…”