Urokinase is required for T lymphocyte proliferation and activation in vitro

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We have previously demonstrated that urokinase-deficient (uPA−/−) mice do not increase lung T lymphocyte number and fail to mount protective immune responses during pulmonary Cryptococcus neoformans infection. These observations suggest a previously unconsidered role for urokinase-type plasminogen activator (uPA) in T lymphocyte-mediated immune responses. Accordingly, we sought to determine whether uPA is required for T cell receptor-mediated (TCR-mediated) lymphocyte proliferation and activation. Splenocytes from uPA−/− and uPA+/+ mice were stimulated with concanavalin A (Con A). The uPA−/− mice had diminished T cell proliferation as compared with uPA+/+ mice. Coculturing uPA−/− T cells with uPA+/+ accessory cells led to the restoration of proliferation. Similarly, T cell proliferation induced by CD3 cross-linking was diminished in uPA−/− mice as compared with uPA+/+ mice. T lymphocyte activation, defined as the induced expression of antigens and the elaboration of cytokines, was determined. The expression of CD69 and that of CD49d were diminished in response to Con A stimulation in uPA−/− mice as compared with uPA+/+ mice. The elaboration of cytokines in response to Con A was also altered in the uPA−/− mice. The production of the Th1 cytokines interferon-γ and interleukin-12 was diminished in uPA−/− mice as compared with uPA+/+ mice. The uPA−/− mice produced increased amounts of interleukin-10, a Th2 cytokine. We conclude that the lack of uPA results in impaired T cell activation and proliferation in response to TCR-mediated signaling and the expression of a less Th1-polarized profile of cytokines. These findings suggest that the inability of uPA−/− mice to combat Cryptococcus neoformans infection may be caused by the impairment of T lymphocyte immune responses in the absence of uPA.