At first, the observation that partial depletion of expanded γδ T cells in the immunized T cells enhances the generation of Th17 IRBP-specific T cells appeared not to be compatible with our previous observation that injection of a small number of γδ T cells into TCR-δ
−/− mice enhances the generation of Th-17 IRBP-specific T cells.
6 We previously reported that the relative frequency of γδ T cells increases greatly in the draining lymph nodes and spleens of immunized mice and increases further during in vitro culture under Th17-polarized conditions.
6 We therefore postulated that, in the early phase of the immune response, the activation and expansion of γδ T cells favor a faster and stronger Th-17 response, but, once the percentage of γδ T cells reaches an optimum, any further increase may suppress the immune response. As a result, the addition to γδTCR
−/− mice of γδ T cells promotes the response, and partial depletion of an excessive number of γδ T cells from immunized mice promotes the generation of IL-17
+ IRBP-specific T cells. Such a prediction was supported by our in vitro study, in which the addition of a low percentage of γδ T cells to responder αβ T cells enhanced, and the addition of a high percentage of γδ T cells suppressed, the response of αβTCR
+IL-17
+ IRBP-specific T cells. Our studies show that γδ T cells have a dual effect on the generation of IL-17
+ αβTCR
+ IRBP-specific T cells. Modestly increased numbers of γδ T cells promote, but excessive numbers inhibit, the generation of IL-17
+ αβTCR
+ IRBP-specific T cells. In 10 separate experiments, approximately half the results were similar to those seen in
Figure 5A, and the rest of the results were similar to those seen in
Figure 5B. As shown, the percentage of γδ T cells among the total responder T cells varied significantly between experiments, and the appearance of a higher proportion of γδ T cells was followed by significantly weaker expansion of IL-17
+ αβTCR
+ T cells. At this point, we are unable to determine the exact factors causing the variation in γδ T-cell numbers between experiments. However, previous studies have shown that components in the mycobacteria and pertussis toxin play a major role regulating γδ T-cell activation in immunized animals.
11,39 It remains to be determined whether minimal change in the use of mycobacteria between experiments has led to the observed variation. These studies demonstrate the complex regulatory effect of γδ T cells on the adaptive immune response. Further studies should allow us to determine the underlying mechanism.