Vβ6+ T Cells Are Obligatory for Vaccine-Induced Immunity to Histoplasma capsulatum

Abstract

We examined TCR usage to a protective fragment of heat shock protein 60 from the fungus, Histoplasma capsulatum. Nearly 90% of T cell clones from C57BL/6 mice vaccinated with this protein were Vβ6+; the remainder were Vβ14+. Amino acid motifs of the CDR3 region from Vβ6+ cells were predominantly IxGGG, IGG, or SxxGG, whereas it was uniformly SFSGG for Vβ14+ clones. Short term T cell lines from Vβ6+-depleted mice failed to recognize Ag, and no T cell clones could be generated. To determine whether Vβ6+ cells were functionally important, we eliminated them during vaccination. Depletion of Vβ6+ cells abrogated protection in vivo and upon adoptive transfer of cells into TCR αβ−/− mice. Transfer of a Vβ6+, but not a Vβ14+, clone into TCR αβ−/− mice prolonged survival. Cytokine generation by Ag-stimulated splenocytes from immunized mice depleted of Vβ6+ cells was similar to that of controls. The efficacy of the Vβ6+ clone was associated with elevated production of IFN-γ, TNF-α, and GM-CSF compared with that of the Vβ14+ clone. More Vβ6+ cells were present in lungs and spleens of TCR αβ−/− on day 3 postinfection compared with Vβ14+ cells. Thus, a single Vβ family was essential for vaccine-induced immunity. Moreover, the mechanism by which Vβ6+ contributed to protective immunity differed between unfractionated splenocytes and T cell clones.

The Protective Immune Response to Heat Shock Protein 60 ofHistoplasma capsulatumIs Mediated by a Subset of Vβ8.1/8.2+ T Cells

“…Following immunization with F3, only V␤6 ϩ and V␤14 ϩ T cells are isolated from infected mice. Depletion of V␤6 ϩ cells causes a complete abrogation in the protective response of F3 immunization, indicating that these cells are functionally required for the protective response to F3 (18). Immunization with rHsp60 produced a very different profile in the TCR repertoire compared with immunization with F3 in the same strain of mouse.…”

“…On the other hand, V␤4 ϩ and 6 ϩ cells are important in secondary infection (17). The expansion of V␤6 ϩ T cells also occurs following immunization with the protective Ag F3, and they play an integral role in the protective response to this Ag (18).…”

Diversity of the T-Cell Response to PulmonaryCryptococcus neoformansInfection

“…Pulmonary infection of mice with H. capsulatum leads to significant skewing of the TCR V␤ repertoire, as does protective vaccination with H. capsulatum heat shock protein 60 (9,10,23). Depletion of the preferentially expanded population in either case adversely affects clearance (9,10,23). Evidence obtained with other experimental systems, however, suggests that V␤ preferences during primary infection are the exception rather than the rule.…”

“…CD4 Our studies demonstrated that a diverse TCR V␤ repertoire is maintained throughout the primary response, but focusing of the TCR V␤ repertoire occurred in CD4 ϩ T-cell populations of individuals during the secondary immune response. Pulmonary infection of mice with H. capsulatum leads to significant skewing of the TCR V␤ repertoire, as does protective vaccination with H. capsulatum heat shock protein 60 (9,10,23). Depletion of the preferentially expanded population in either case adversely affects clearance (9,10,23).…”

“…Somatic recombination of diversity and joining regions in V␣ and somatic recombination of variable, diversity, and joining regions in V␤ result in the diversity of the TCR repertoire (3). A number of studies, including studies of the pathogenic fungus Histoplasma capsulatum, have demonstrated that there are V␤ preferences during T-cell responses, which correlate to T-cell function or antigen specificity (7)(8)(9)(10)(11). Similar to control of C. neoformans infection, control of H. capsulatum infection is primarily dependent on CD4 ϩ T cells.…”