The p110 delta isoform of phosphatidylinositol 3-kinase controls the quality of secondary anti-Leishmania immunity by regulating expansion and effector function of memory T cell subsets.
We showed previously that mice with an inactivating knockin mutation in the p110delta isoform of PI3K (referred to as p110delta(D910A) mice) displayed enhanced primary resistance to Leishmania major despite mounting paradoxically impaired T cell responses. In this study, we show that p110delta(D910A) mice are impaired in their secondary (memory) anti-Leishmania responses in vitro and in vivo. Following secondary L. major challenge, p110delta(D910A) mice exhibited reduced delayed-type hypersensitivity response and weaker parasite control compared to wild-type mice. Using adoptive transfer experiments, we show that immune T cells from healed p110delta(D910A) mice were impaired in their proliferation and effector cytokine (IFN-gamma) responses upon L. major challenge. Interestingly, Leishmania-reactive T cells from healed p110delta(D910A) mice contain severalfold lower numbers of CD62L(lo) and CD62(hi) T cells than those from healed wild-type mice. The reduction in numbers of CD62L(lo) T cells in p110delta(D910A) mice is due to failure of their CD62L(hi) T cells to downregulate CD62L expression in response to L. major. Furthermore, although CD62L(lo) cells from p110delta(D910A) mice could home efficiently to lymphoid organs, their ability to exit these tissues and emigrate to cutaneous sites of infection was greatly impaired. Collectively, our data identify PI3K signaling as important events that control memory T cell subset differentiation, generation, effector function, and recruitment to cutaneous tissues and suggest that manipulating this pathway could provide means of enhancing desired memory T cell subset, response during vaccination, or both.
Department of Immunology, University of Manitoba, Winnipeg, Manitoba, Canada.
Dong
D
Liu
Jude E
JE
Uzonna
D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D058534:Class I Phosphatidylinositol 3-Kinases; D016207:Cytokines / Q000096:biosynthesis / Q000172:deficiency; D015536:Down-Regulation / Q000235:genetics / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000276:immunology; D055879:Gene Knock-In Techniques; D020868:Gene Silencing / Q000276:immunology; D006968:Hypersensitivity, Delayed / Q000201:enzymology / Q000276:immunology / Q000469:parasitology; D007117:Immunization, Secondary / Q000379:methods*; D007156:Immunologic Memory / Q000235:genetics; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D018320:Leishmania major / Q000276:immunology*; D016773:Leishmaniasis, Cutaneous / Q000201:enzymology* / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016052:Protozoan Vaccines / Q000008:administration & dosage / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000201:enzymology* / Q000276:immunology* / Q000469:parasitology
D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D007527:Isoenzymes; D016052:Protozoan Vaccines; D019869:Phosphatidylinositol 3-Kinases; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse; D058534:Class I Phosphatidylinositol 3-Kinases