Activation of resting human CD4+ "naive" (CD45RA+CD45RO-) and "memory" (CD45RA-CD45RO+) T cells requires costimulatory signals in addition to engagement of the T cell receptor/CD3 complex (TCR/CD3). The adhesion pathways mediated by lymphocyte function-associated antigen 1/intercellular adhesion molecule 1 (LFA-1/ICAM-1) and CD2/LFA-3 are capable of providing such costimulatory signals. Our work shows that these costimulatory adhesion pathways are critically involved in regulation of T cell differentiation/maturation. Evidence for subset-specific costimulatory requirements is demonstrated by the finding that only memory CD4+ T cells were costimulated by LFA-3, whereas both naive and memory CD4+ T cells were costimulated by ICAM-1. In addition, these costimulatory adhesion pathways regulated reciprocal cytokine secretion patterns for interleukin 5 (IL-5) and granulocyte/macrophage colony-stimulating factor (GM-CSF). Repeated costimulation of CD4+ memory T cells with LFA-3 led to secretion of high levels of IL-5, while repeated costimulation with ICAM-1 induced high levels of secreted GM-CSF. Significant interferon gamma (IFN-gamma) production was observed with either of the costimulatory ligands. Extensive cell surface analysis of these in vitro cultures of peripheral blood derived memory CD4+ T cells, with monoclonal antibodies obtained from the 5th Leucocyte Typing Workshop, revealed differential expression of a singular antigen, CD60. This antigen was preferentially expressed on LFA-3-costimulated cells suggesting a positive correlation between CD60 expression and a T helper type 2-like cytokine profile. In conclusion, this report demonstrates a new functional role for costimulatory adhesion molecules in regulating differential cytokine secretion in human memory CD4+ T cells.

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