Lymphomas arising from NK or gd-T cells are very aggressive diseases and little is known regarding their pathogenesis. Here we report frequent activating mutations of STAT3 and STAT5B in NK/T-cell lymphomas (n ¼ 51), gd-T-cell lymphomas (n ¼ 43) and their cell lines (n ¼ 9) through next generation and/or Sanger sequencing. STAT5B N642H is particularly frequent in all forms of gd-T-cell lymphomas. STAT3 and STAT5B mutations are associated with increased phosphorylated protein and a growth advantage to transduced cell lines or normal NK cells. Growth-promoting activity of the mutants can be partially inhibited by a JAK1/2 inhibitor. Molecular modelling and surface plasmon resonance measurements of the N642H mutant indicate a marked increase in binding affinity of the phosphotyrosine-Y699 with the mutant histidine. This is associated with the prolonged persistence of the mutant phosphoSTAT5B and marked increase of binding to target sites. Our findings suggest that JAK-STAT pathway inhibition may represent a therapeutic strategy.

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Morphological and functional heterogeneity of the splenic macrophage (Mf) population was studied in Leishmania donovani (LD) infected BALB/c mice. On a discontinuous percoll gradient two distinct Mf populations were separated. They differed significantly in size as evident from Scanning Electron Microscopy (SEM). Morphologically, the bigger Mf (LM) showed surface projections, whereas the smaller Mf (SM) was round. As regards the antigen-presenting abilities, the LM of infected animals showed defective antigen-presenting abilities at a later stage of the disease, i.e. 6 months post infection ( 6 I-LM) but not earlier, whereas the SM population remained functionally intact throughout the course of the infection. Further, the 6 I-LM showed a much enhanced A d status as compared to their controls. Interestingly, both the 6 I-LM and the control set showed a comparable level of binding of a known A d restricted peptide. Despite the presence of sufficient A d molecules and the ability to bind the appropriate peptide, 6 I-LM were unable to stimulate peptide specific T-cell hybridoma. Further, the 6 I-LM showed an increase in membrane fluidity and distorted morphology with membrane fissure and blebs as evident from SEM. It is possible that an increase in the membrane fluidity may lead to the defective antigen-presenting ability of 6 I-LM. Thus, the LD infection functionally keep the 6 I-LM out of antigen presentation and this may contribute to the defective cell mediated immune response in leishmaniasis.

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