Differential requirement for the CD45 splicing regulator hnRNPLL for accumulation of NKT and conventional T cells

Natural killer T (NKT) cells represent an important regulatory T cell subset that develops in the thymus and contains immature (NK1.1(lo)) and mature (NK1.1(hi)) cell subsets. Here we show in mice that an inherited mutation in heterogeneous ribonucleoprotein L-like protein (hnRNPLL(thunder)), that shortens the survival of conventional T cells, has no discernible effect on NKT cell development, homeostasis or effector function. Thus, Hnrpll deficiency effectively increases the NKT∶T cell ratio in the periphery. However, Hnrpll mutation disrupts CD45RA, RB and RC exon silencing of the Ptprc mRNA in both NKT and conventional T cells, and leads to a comparably dramatic shift to high molecular weight CD45 isoforms. In addition, Hnrpll mutation has a cell intrinsic effect on the expression of the developmentally regulated cell surface marker NK1.1 on NKT cells in the thymus and periphery but does not affect cell numbers. Therefore our results highlight both overlapping and divergent roles for hnRNPLL between conventional T cells and NKT cells. In both cell subsets it is required as a trans-acting factor to regulate alternative splicing of the Ptprc mRNA, but it is only required for survival of conventional T cells.This work was supported by the National Institutes of Health (NIH) contract BAA NIAID-DAIT-07-35; Juvenile Diabetes Research Foundation/National Health and Medical Research Council (JDRF/NHMRC) Special Program Grant 219167 and JDRF Program Grant 7-2006-327. Dr. Yabas was supported by a postgraduate award from the Ministry of National Education, Republic of Turkey, Dr. Godfrey by an NHMRC Principal Research Fellowship and Dr. Goodnow by an Australian Research Council (ARC) Federation Fellowship. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript