MIP is a nonpathogenic, soil-borne predecessor of Mycobacterium avium. It has been reported previously that MIP possesses strong immunomodulatory properties and confers protection against experimental TB and tumor. DCs, by virtue of their unmatched antigen-presentation potential, play a critical role in activation of antitumor and antimycobacterial immune response. The effect of MIP on the behavior of DCs and the underlying mechanisms, however, have not been investigated so far. In the present study, we showed that MIP induces significant secretion of IL-6, IL-12p40, IL-10, and TNF-α by DCs and up-regulates the expression of costimulatory molecules CD40, CD80, and CD86. MIP(L) induced a significantly higher response compared with MIP(K). PI and Annexin V staining showed that MIP increases DC survival by inhibiting apoptosis. Consistently, higher expression of antiapoptotic proteins Bcl-2 and Bcl-xl was observed in MIP-stimulated DCs. Cytokines, produced by naïve T cells, cocultured with MIP-stimulated DCs, showed that MIP promotes Th1/Th17 polarization potential in DCs. Response to MIP was lost in MyD88(-/-)DCs, underscoring the critical role of TLRs in MIP-induced DC activation. Further studies revealed that TLR2 and TLR9 are involved in DC activation by MIP(L), whereas MIP(K) activates the DCs through TLR2. Our findings establish the DC activation by MIP, define the behavior of MIP-stimulated DCs, and highlight the role of TLRs in MIP-induced DC activation.

Immune dysfunction is critical in pathogenesis of cutaneous T-cell lymphoma (CTCL). Few studies have reported abnormal cytokine profile and dysregulated T-cell functions during the onset and progression of certain types of lymphoma. However, the presence of IL9-producing Th9 cells and their role in tumor cell metabolism and survival remain unexplored. With this clinical study, we performed multidimensional blood endotyping of CTCL patients before and after standard photo/chemotherapy and revealed distinct immune hallmarks of the disease. Importantly, there was a higher frequency of "skin homing" Th9 cells in CTCL patients with early (T1 and T2) and advanced-stage disease (T3 and T4). However, advancedstage CTCL patients had severely impaired frequency of skin-homing Th1 and Th17 cells, indicating attenuated immunity. Treatment of CTCL patients with standard photo/ chemotherapy decreased the skin-homing Th9 cells and increased the Th1 and Th17 cells. Interestingly, T cells of CTCL patients express IL9 receptor (IL9R), and there was negligible IL9R expression on T cells of healthy donors. Mechanistically, IL9/IL9R interaction on CD3 þ T cells of CTCL patients and Jurkat cells reduced oxidative stress, lactic acidosis, and apoptosis and ultimately increased their survival. In conclusion, coexpression of IL9 and IL9R on T cells in CTCL patients indicates the autocrine-positive feedback loop of Th9 axis in promoting the survival of malignant T cells by reducing the oxidative stress. Implications:The critical role of Th9 axis in CTCL pathogenesis indicates that strategies targeting Th9 cells might harbor significant potential in developing robust CTCL therapy.

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Vitiligo is an acquired idiopathic depigmentation disorder where selective damage of functional melanocytes causes hypo-pigmentation of the skin, hair, and mucosal surface (Ezzedine et al., 2015). The CD4 + and CD8 + T cells are described to be present at the junction of epidermis and dermis near the lesional skin of vitiligo, and the cytotoxic T cells are reported to kill melanocytes in vitiligo, emphasizing the roles of T cell-mediated immunity in vitiligo pathogenesis (van den Boorn et al., 2009). Recognizing imbalanced and dysfunctional effector T-cell subsets as well as dysregulated cytokine production might harbor significant potential for the targeted therapy. In addition, there are many indistinct facts about the loss of self-tolerance and dysregulated cytokine production in vitiligo pathogenesis.