Intracellular Analysis of Interleukin-2 Induction Provides Direct Evidence at the Single Cell Level of Differential Coactivation Requirements for CD45RA+ and CD45RO+ T Cell Subsets

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Abstract
Through measurements of intracellular cytokine production, evidence is provided at the single cell level that triggering different cell surface molecules preferentially activates discrete human peripheral blood (PB) T cell subsets. T cell costimulation due to cross-linking a variety of individual molecules (beta1, beta2, and beta7 integrins, CD26, CD43, or CD44), in conjunction with the CD3/TCR complex, preferentially activated CD45RO+ PB T lymphocytes. CD28, however, costimulated interleukin-2 (IL-2) production in both CD45RO+ and CD45RA+ subpopulations. The amount of soluble IL-2 produced by CD28 coactivation was 15-30-fold higher than that due to integrin or CD26-dependent coactivation, although even the lowest amount of soluble IL-2 produced was in the range of the high-affinity IL-2 receptor. The overall proliferative responses were similar among all costimulatory settings. This was in part due to the uniform upregulation of IL-2 receptor-alpha (IL-2Ralpha) (CD25) expression on the entire T cell population activated under each of the different costimulatory conditions. The data provide direct evidence on a single cell level that activation of human CD45RA+ (naive) T cells is stringently controlled and, in these studies, limited to CD28 costimulation for induction of IL-2 production. In contrast, coactivation of CD45RO+ (memory) T lymphocytes can proceed by a variety of different PB T cell surface molecules.