Submitted March 14, 2006
Accepted October 5, 2006
Cytotoxic CD4+ T cells use granulysin to kill Cryptococcus neoformans and activation of this pathway is defective in HIV patients
Chun Fu Zheng, Lingling Ma, Gareth J Jones, M John Gill, Alan M. Krensky, Paul Kubes, and Christopher H Mody*
University of Calgary, Canada
Stanford University Medical Center
* Corresponding author; email: cmody{at}ucalgary.ca.
An important mechanism of host defense to Cryptococcus neoformans involves the direct microbicidal activity of lymphocytes. The importance of CD4+ T cells is illustrated by the incidence of this infection in AIDS patients; however, the relative activity of microbicidal CD4+ T cells compared to CD8+ T cells and NK cells has not been established. Further, although NK cells and CD8+ T cells utilize perforin or granulysin respectively to kill C. neoformans, the effector molecule used by CD4+ T cells is not known. Experiments demonstrated that IL-2-activated peripheral blood lymphocytes from healthy adults acquire anti-cryptococcal activity, and surprisingly, that CD4+ T cells had the most profound effect on this activity. Using SrCl2-induced degranulation and siRNA knockdown, granulysin, was shown to be the effector molecule. Although activation by anti-CD3+IL-2 resulted in the additional expression of perforin, this did not improve the anticryptococcal activity. Cryptococcal killing by CD4+ T cells was defective in HIV-infected patients due to dysregulated granulysin and perforin production in response to IL-2 or anti-CD3+IL-2. In conclusion, CD4+ T cells are the major subset of cells responsible for killing C. neoformans in peripheral blood. These cells use granulysin as the effector molecule, and priming is dysregulated in HIV-infected patients, which results in defective microbicidal activity.
