Lymphotoxin alpha beta Is Expressed on Recently Activated Naive and Th1-like CD4 Cells but Is Down-Regulated by IL-4 During Th2 Differentiation

Lymphotoxin (LT) is a cytokine that orchestrates lymphoid neogenesis and formation of germinal center reactions. LT exists as a membrane heterotrimer of alpha and beta subunits and is secreted as a homotrimer, LT alpha 3. Using LTssR.Fc, expression of LT alpha beta on CD4 T cell subsets was investigated in a TCR transgenic model. LT alpha beta was evident 24-72 h after activation of naive T cells with specific Ag, and declined thereafter. Early expression was independent of IFN- gamma and IL-12, however, IL-12 prolonged expression. LT alpha beta was reinduced within 2-4 h after Ag restimulation, but declined by 24 h regardless of IL-12 or IFN- gamma priming. Exposure of naive T cells to IL-4 did not affect early LT alpha beta expression at 24 h, but resulted in subsequent down-regulation. IL-4-differentiated Th2 effectors did not re-express LT alpha beta , and LT alpha beta was transiently found on Th1 clones but not Th2 clones. LT alpha 3 and TNF were immunoprecipitated from supernatants and lysates of IL-12 primed cells but not IL-4 primed cells. These studies demonstrate that LT alpha beta is expressed by activated naive CD4 cells, unpolarized IL-2-secreting effectors, and Th1 effectors. In contrast, loss of surface LT alpha beta and a lack of LT alpha 3 and TNF secretion is associated with prior exposure to IL-4 and a Th2 phenotype.