Ablation of CD8 and CD4 T Cell Responses by High Viral Loads

Abstract

To evaluate the impact of sustained viral loads on anti-viral T cell responses we compared responses that cleared acute lymphocytic choriomeningitis virus infection with those that were elicited but could not resolve chronic infection. During acute infection, as replicating virus was cleared, CD8 T cell responses were down-regulated, and a pool of resting memory cells developed. In chronically infected hosts, the failure to control the infection was associated with pronounced and prolonged activation of virus-specific CD8 T cells. Nevertheless, there was a progressive diminution of their effector activities as their capacity to produce first IL-2, then TNF-α, and finally IFN-γ was lost. Chronic lymphocytic choriomeningitis virus infection was also associated with differential contraction of certain CD8 T cell responses, resulting in altered immunodominance. However, this altered immunodominance was not due to selective expansion of T cells expressing particular TCR Vβ segments during chronic infection. High viral loads were not only associated with the ablation of CD8 T cell responses, but also with impaired production of IL-2 by virus-specific CD4 T cells. Taken together, our data show that sustained exposure to high viral loads results in the progressive functional inactivation of virus-specific T cell responses, which may further promote virus persistence.

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virus-specific CD8 + T cells during chronic infection due to continued antigen encounter ( [40,54] and Agnellini et al, unpublished observations), which might be dependent on IL-2R signaling.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generally unable to produce measurable amounts of IL-2 during chronic viral infection ( [30,31,55] and Agnellini et al, unpublished observations).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).…”

Immunoproteasome-Deficient Mice Mount Largely Normal CD8+ T Cell Responses to Lymphocytic Choriomeningitis Virus Infection and DNA Vaccination

“…5). Third, the authors proposed that skewing the CD8 ϩ T cell response in favor of gp276-specific responses, as seen in chronic LCMV infection (34,35), could be due to the down-regulation of immunoproteasomes in chronic infection, leading to the enhanced generation of gp276 molecule was determined on the four indicated cell types in WT and LMP2KO mice in three different circumstances with respect to virus infection: naive, day 8 after primary infection, and day 4 after secondary challenge. B, WT mice (u) and LMP2KO mice (Ⅺ) received two doses of NP 205 peptide vaccine (vac; p) as described in Materials and Methods; control mice were not vaccinated.…”

IL‐7 is superior to IL‐2 for ex vivo expansion of tumour‐specific CD4+ T cells

“…While, Ag tumours elicit natural tumour-specific CD4 1 T-cell responses [4][5][6][7][8][9][10], functional tolerance is eventually observed through the induction of T-cell anergy [11,12], T-cell depletion [13] or the limitation of the memory repertoire [10,14,15]. This is possibly due to Ag persistence, and continual TCR signaling, as in the case of chronic viral infections [16][17][18]. In addition, regulatory CD4 1 T cells have been frequently found in the case of tumours, often among the tumour-infiltrating lymphocytes, thereby persuading the general interest towards CD8 1 CTL.…”

“…viral infections [16][17][18]. In addition, regulatory CD4 1 T cells have been frequently found in the case of tumours, often among the tumour-infiltrating lymphocytes, thereby persuading the general interest towards CD8 1 CTL.…”