E protein activity regulates effector lineage differentiation of NKT and ILCs

Oklahoma Medical Research Foundation, Oklahoma City OK

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Abstract

? DESCRIPTION (provided by applicant): Classically the immune system has been divided into adaptive and innate systems, differentiated by the use of clonally-specific antigen-specific receptors generated by genetic recombination vs. non-diverse receptors that recognize evolutionary conserved pathogen molecules. The former requires more time to mount an effective response, but has memory, while the latter responds rapidly, and has no memory. Most components of the innate immune system derive from myeloid precursors, while the adaptive immune system derives from lymphoid precursors. However, there are a number of lymphoid cells that straddle these categories. The classic example are NK cells, lymphocytes that develop from CLPs but recognize pathogen using germ line-encoded receptors and exist in a primed state. In the last few year an increasing number of other innate lymphoid cells have been identified, including ILCs (innate lymphoid cells), as well as some cells that express rearranged antigen receptors, such as NKTs, and some ?? T cells. The roles and significance of these populations in normal immune responses and pathology is an underexplored area of great interest. Some of these innate lymphoid cells, especially ILCs and NKTs share developmental and effector programs with conventional helper T cells. The Th1, Th2, and Th17 programs share properties with the ILC1, ILC2, ILC3 and the NKT1, NKT2, and NKT17 programs, respectively. Since different mouse strains have significantly different distributions of these lineages, it is clear that genetic factors contribute to the differentiation across these alternative effector fates, but the molecular mechanisms that determine the representation of each effector type within each population are unknown, as is whether these mechanisms are common for the different lineages. Recent experiments from our group suggest that changes in E protein activity in developing NKT cells substantially bias effector lineage differentiation. Increasing E protein activity in C57BL/6 thymocytes results in a change from a predominant NKT1 differentiation profile to a NKT2/NKT17 profile. In this project we will 1) test this model by trying to convert the predominant NKT2 differentiation pattern in Balb/c mice to NKT1 by decreasing E protein activity in DP thymocytes. 2) analyze whether E protein activity plays a similar role during ILC differentiation.