A Deficiency in Gamma Interferon or Interleukin-10 Modulates T-Cell-Dependent Responses to Heat Shock Protein 60 fromHistoplasma capsulatum

Abstract

Immunization of mice with heat shock protein 60 from Histoplasma capsulatum or a polypeptide from the protein designated F3 confers protection. V␤8.1/8.2 ؉ T cells are critically important for the protective efficacy of this antigen. The production of interleukin-10 and gamma interferon following vaccination is essential for efficacy. In this study, we sought to determine whether the absence of either cytokine modified the repertoire of antigen-reactive T cells and whether it altered the functional properties of T cells. Mice lacking gamma interferon or interleukin-10 manifested a skewed repertoire compared to that of wild-type mice. The bias was most marked in gamma interferon-deficient mice and modestly altered in interleukin-10-deficient animals. The altered repertoire in gamma interferon-deficient mice could not be explained at the level of antigen presentation or by the absence of this population from mice. The proportion of T cells from interleukin-10-deficient mice manifesting a Th1 phenotype was greatly increased compared to that from wild-type animals. Transfer of splenocytes from gamma interferon-or interleukin-10-deficient mice immunized with heat shock protein 60 failed to confer protection in T-cell receptor ␣/␤ ؊/؊ mice. The transfer of T-cell clones that did not produce both cytokines failed to prolong survival in T-cell receptor ␣/␤ ؊/؊ mice, whereas the clones with the same features that were derived from wild-type mice did. These results indicate that the cytokine milieu influences the shape of the T-cell receptor repertoire and support the importance of gamma interferon and interleukin-10 in the efficacy of heat shock protein 60.

Vaccination with Heat Shock Protein 60 Induces a Protective Immune Response against ExperimentalParacoccidioides brasiliensisPulmonary Infection

“…Our previous studies in vaccination with H. capsulatum Hsp60 also demonstrated a dominant Th1 response as manifested by IFN-␥ release (18). In the absence of this cytokine, vaccine efficacy is abrogated and there is a major shift in the clonal phenotype and function of T cells (44). Differences did emerge between H. capsulatum HSP60 and PbHSP60.…”

“…Although the FIII fraction induces IFN-␥, this property did not result in protection against the challenge infection (21,23). Previously, we had identified H. capsulatum HSP60 as a prominent target of T-cell-mediated immunity and a protective vaccine in experimental pulmonary histoplasmosis (18,44). Given the high level of evolutionary conservation among the HSP family, and particularly among the H. capsulatum and P. brasiliensis HSP60 gene and protein sequences, we postulated that PbHSP60 would share some of the immunobiologic properties of H. capsulatum HSP60.…”

The role of immunostimulation in the treatment of invasive fungal infection

“…The addition of CD40L in vaccination of CD4-depleted mice results in antibody responses similar to those in CD4-repleted mice [45]. As the production of IFN-and IL-10 following vaccination is essential for efficacy, it is appropriate to concentrate on vaccination strategies that stimulate the survival and activity of Treg that fine-tune protective responses in the absence of immune pathology [46]. Hsps may be also promising in fungal vaccine development as they induce antibody and type I cellular immunity [47].…”

Attempts at a peptide vaccine against paracoccidioidomycosis, adjuvant to chemotherapy

“…In the immune response against HSP60 from Histoplasma capsulatum or a polypeptide fraction from this protein (F3), production of IL-10 and IFN-c was essential for therapy efficacy. Apparently in this particular case, the cytokine milieu determines the conformation of TCRs making Vb8.1/8.2 + T cells essential for the protective effect of HSP60 [24].…”