High-Avidity CTL Exploit Two Complementary Mechanisms to Provide Better Protection Against Viral Infection Than Low-Avidity CTL

Abstract

Previously, we observed that high-avidity CTL are much more effective in vivo than low-avidity CTL in elimination of infected cells, but the mechanisms behind their superior activity remained unclear. In this study, we identify two complementary mechanisms: 1) high-avidity CTL lyse infected cells earlier in the course of a viral infection by recognizing lower Ag densities than those distinguished by low-avidity CTL and 2) they initiate lysis of target cells more rapidly at any given Ag density. Alternative mechanisms were excluded, including: 1) the possibility that low-avidity CTL might control virus given more time (virus levels remained as high at 6 days following transfer as at 3 days) and 2) that differences in efficacy might be correlated with homing ability. Furthermore, adoptive transfer of high- and low-avidity CTL into SCID mice demonstrated that transfer of a 10-fold greater amount of low-avidity CTL could only partially compensate for their decreased ability to eliminate infected cells. Thus, we conclude that high-avidity CTL exploit two complementary mechanisms that combine to prevent the spread of virus within the animal: earlier recognition of infected cells when little viral protein has been made and more rapid lysis of infected cells.

CD8+ T cells, NK cells and IFN-γ are important for control of tumor with downregulated MHC class I expression by DNA vaccination

“…22,23 This so-called functional avidity maturation may occur though cross-linking of receptors, 24 activation-induced cholesterol enrichment of membranes, 24 or changes in signal transduction. 22,25 Studies have revealed that higher avidity T cells generate stronger antigen-specific antiviral 26,27 or antitumor 9,18,19 effects. Derby et al 27 observed that following viral infection, high-avidity CTL mediate earlier antigen recognition because of higher sensitivity to antigen than low-avidity T cells and initiate antigen-specific lysis more rapidly than low-avidity T cells.…”

Estimation of low frequency antigen-presenting cells with a novel RELISPOT assay

“…DCs were grown from bone marrow by cultivating in CM with 1µg/ml GMCSF for 5 days. The P18-I10-specific T-cell line MHb (Derby et al, 2001a) was maintained in CM containing 10% T-Stim Culture Supplement (BD Biosciences, San Jose, CA). Every 10 days T cells were restimulated with addition 0.5 nM P18-I10 peptide and irradiated splenocytes from BALB/c mice.…”

A stochastic model of cytotoxic T cell responses

“…It also includes a term for inter-clonal competition among the effector cells for infected cells expressing a single epitope. It appears that high-and low-avidity CTL lyse their targets at similar rates (Derby et al, 2001), so we set k c to be the same for all T cell clones in our model. In LCMV responses, the value of k c was found to be 12 day À1 (Barchet et al, 2000).…”