T helper 2 differentiation is necessary for development of lymphedema

T cells infiltrating lymphedematous tissues have a mixed T helper 1 (Th1) and Th2 differentiation profile. Treatment with neutralizing antibodies targeting cytokines that promote Th2 differentiation (interleukin 4 [IL-4] and IL-13) decreases the severity of lymphedema in preclinical models, suggesting that Th2 cells play a key role in the pathology of this disease. However, these previous studies do not address the contribution of Th1 cells and it remains unknown if IL-4 and IL-3 blockade acts primarily on T cells or decreases the pathological changes of lymphedema by other mechanisms. Therefore, this study sought to analyze the effect of lymphatic injury in transgenic mice with mutations that cause defects in Th1 and Th2 cell generation (T-bet knockout or T-betKO and STAT6 knockout or STAT6KO mice, respectively). Using both the mouse tail and popliteal lymph node dissection models of lymphedema, we show that Th2-deficient (STAT6KO) mice are protected from developing lymphedema, have decreased fibrosis, increased collateral vessel formation, and preserved collecting lymphatic vessel pumping function. In contrast, mice with defective Th1 cell generation (T-betKO) develop disease with the same severity as wild-type controls. Taken together, our results suggest that Th2 differentiation is necessary for development of lymphedema following lymphatic injury and that Th1 differentiation does not significantly contribute to the pathology of the disease. Such findings are important as immunotherapy directed at Th2 cells has been found to be effective in well-studied Th2-mediated diseases such as asthma and atopic dermatitis and may therefore be similarly useful for lymphedema management.