Epitope Specificity and Relative Clonal Abundance Do Not Affect CD8 Differentiation Patterns during Lymphocytic Choriomeningitis Virus Infection

Abstract

To evaluate the impact of immunodominance on CD8 T-cell properties, we compared the functional properties of dominant and subdominant populations in the response to lymphocytic choriomeningitis virus (LCMV). To improve functional discrimination, in addition to the usual tests of phenotype and function, we used a sensitive technique that allows the screening of all CD8 effector genes simultaneously in single cells. Surprisingly, these methods failed to reveal a major impact of clonal dominance in CD8 properties throughout the response. Aiming to increase clonal dominance, we examined high-frequency transferred P14 T-cell receptor transgenic (TCR Tg) cells. Under these conditions LCMV is cleared faster, and accordingly we found an accelerated response. However, when Tg and endogenous cells were studied in the same mice, where they should be subjected to the same antigen load, they showed overlapping properties, and the presence of P14 cells did not modify endogenous responses to other LCMV epitopes or a perturbed immunodominance hierarchy in the memory phase. Using allotype-labeled Tg cells, we found that during acute infection up to 80% downregulated their TCR and were undetectable by tetramer binding, and that tetramer-negative and tetramer-positive cells had very different features. Since Tg cells are not available to evaluate immune responses in humans and, in many cases, are not available from the mouse, the tetramer-based evaluation of early immune responses in most situations of high viremia may be incomplete and biased.

The Influenza Virus–Specific CTL Immunodominance Hierarchy in Mice Is Determined by the Relative Frequency of High-Avidity T Cells

“…PB1-F2 62 emerges relatively late in the response. Although not as striking as the influenza results presented in this study, the observation that naive CTLps do not exhibit synchronized proliferation to establish an acute-phase immunodominance hierarchy is supported by other studies that have analyzed the evolution of archetypal CTL immunodominance hierarchies to LCMV and Listeria monocytogenes (38)(39)(40). These studies showed that the relative magnitudes of epitopespecific CTL populations differed early, compared with at the peak of the established response.…”

CD70 Deficiency Impairs Effector CD8 T Cell Generation and Viral Clearance but Is Dispensable for the Recall Response to Lymphocytic Choriomeningitis Virus

“…4A), a slightly lower capacity to secrete cytokines in CD70 x−/− cells probably also contributed. It is also possible that some antigen-specific cells were unaccounted for due to TCR-downregulation (50). T-bet and Eomes, transcription factors that govern the CD8 T cell cytotoxic program, and the majority of surface markers of differentiation, such as CD122 (β component of IL-2 and IL-15 cytokine receptors), CD25 (β component of IL-2 receptor), and Ly6C, were indistinguishable between the strains at the peak of the response (Fig.…”

Chronic HIV infection affects the expression of the 2 transcription factors required for CD8 T-cell differentiation into cytolytic effectors

“…It is possible that CD8 T cells only produce these mediators when they are in direct contact with antigen-presenting cells in different tissues. However, in mice infected with either with LCMV 39 or Listeria monocytogenes, 30 tissue-resident CD8 T cells also rarely produced these mediators. Therefore, the contribution of CD8 T cells to the production of IL-2, TNF-␣, and the chemokine CCL3 during HIV infection remains to be demonstrated.…”