Immunization with a cell wall/membrane (CW/M) and yeast cytosol extract (YCE) crude antigen from Blastomyces dermatitidis confers T-cell-mediated resistance against lethal experimental infection in mice. We isolated and characterized T cells that recognize components of these protective antigens and mediate protection. CD4⁺ T-cell clones elicited with CW/M antigen adoptively transferred protective immunity when they expressed a Vα2⁺ Jα49⁺/Vβ1⁺ Jβ1.1⁺ heterodimeric T-cell receptor (TCR) and produced high levels of gamma interferon (IFN-γ). In contrast, Vβ8.1/8.2⁺ CD4⁺ T-cell clones that were reactive against CW/M and YCE antigens and produced little or no IFN-γ either failed to mediate protection or exacerbated the infection depending on the level of interleukin-5 expression. Thus, the outgrowth of protective T-cell clones against immunodominant antigens of B. dermatitidis is biased by a combination of the TCR repertoire and Th1 cytokine production.