Depletion of γδ + T cells increases CD4 + FoxP3 (T regulatory) cell response in coxsackievirus B3‐induced myocarditis

Summary Coxsackievirus B3 (CVB3) causes severe myocarditis in BALB/c mice which depends upon CD4 +  T helper type 1 [Th1; i.e. interferon‐γ + (IFN‐γ + )] and γδ + cells. Depleting γδ + cells using anti‐γδ antibody suppresses myocarditis and CD4 +  IFN‐γ + cell numbers in the spleen and heart of infected mice while increasing CD4 +  FoxP3 + cells. Mice deficient in γδ + cells have increased numbers of naïve (CD44 lo  CD62L hi ) and fewer effector (CD44 hi  CD62 lo ) memory CD4 + cells than infected γδ + ‐cell‐sufficient mice. Virus neutralizing antibody titres are not significantly different between γδ + T‐cell‐sufficient and ‐deficient animals. To confirm that the memory cell response differs in acutely infected mice lacking γδ + cells, CD4 + cells were purified and adoptively transferred into naïve recipients, which were rested for 4 weeks then infected with CVB3. Recipients given either 0·5 × 10 6 or 1·0 × 10 6 CD4 + from infected donors developed over twice the severity myocarditis and 10‐fold less cardiac virus titre compared with recipients given equivalent numbers of CD4 + cells from infected and γδ + ‐cell‐depleted donor animals. Additionally, to show that more functionally active T regulatory cells are present in γδ + T‐cell‐depleted mice, CD4 +  CD25 + and CD4 +  CD25 − cells were isolated and adoptively transferred into infected recipients. Mice receiving CD4 +  CD25 + cells from γδ + T‐cell‐depleted donors developed significantly less myocarditis and CD4 + Th1 cell responses compared with mice receiving equal numbers of CD4 +  CD25 + cells from infected γδ + T‐cell‐sufficient animals. This study shows that γδ + cells promote CD4 +  IFN‐γ + acute and memory responses by limiting FoxP3 + T regulatory cell activation.