Abstract
T cell immunoglobulin and mucin-4 (TIM-4), mainly expressed on antigen presenting cells, plays a versatile role in immunoregulation. CD1d-restricted invariant natural killer T (iNKT) cells are potent cells involved in the diverse immune responses. It was recently reported that recombinant TIM-4 (rTIM-4) alone enhanced cytokine production in NKT hybridoma, DN32.D3 cells. Hence, we hypothesized that TIM-4 might regulate iNKT cell biology, especially their function of cytokine secretion. For the first time, we identified that TIM-4 was expressed in thymus iNKT cells, and its expression increased upon iNKT cell migration to the secondary lymphoid organs, especially in lymph nodes. Using TIM-4-deficient mice, we found that lack of TIM-4 did not disturb iNKT cell development, maturation, peripheral homeostasis and cytokine secretion. Moreover, TIM-4 deficiency did not alter the polarization of iNKT sublineages, including NKT1, NKT2 and NKT17. Finally, the mixed bone marrow transfer experiments further confirmed normal iNKT cell development and function from TIM-4-deficient bone marrow. In conclusion, our data suggest that TIM-4 is expressed on iNKT cells but dispensable for their development and function.
Highlights
Natural killer T (NKT) cells comprise a unique subset of αβT cells that coexpress a semi-invariant T-cell receptor (TCR) and natural killer (NK) cell-related surface markers
To detect T cell immunoglobulin and mucin-4 (TIM-4) expression in the immature and mature invariant natural killer T (iNKT) cells in different lymphoid organs, lymphocytes from thymus, spleen, skindraining lymph nodes (LN) and liver of T-cell immunoglobulin domain and mucin domain (TIM)-4 KO and wild-type (WT) mice were stained with antibodies against TCR-β, PBS57-CD1d tetramer, NK1.1 and TIM-4
LN iNKT cells expressed TIM-4 at the highest level. Compared with their immature counterparts, mature NK1.1+ iNKT cells in the thymus, spleen and LNs expressed higher levels of TIM-4, there was no significant difference between the NK1.1- and NK1.1+ subsets of LN iNKT cells (Figure 1b)
Summary
Natural killer T (NKT) cells comprise a unique subset of αβT cells that coexpress a semi-invariant T-cell receptor (TCR) and natural killer (NK) cell-related surface markers. They stringently respond to glycolipid antigens, such as α-galactosylceramide (α-GalCer), presented by the major histocompatibility complex (MHC) class I-like molecule CD1d [1]. INKT cells derive from CD4+ CD8+ double-positive (DP) thymus precursors and undergo four distinct stages of differentiation involving sequential downregulation of CD24 and upregulation of CD44 and NK1.1 [6,7,8,9]. The DP thymocytes, expressing Vα14-Jα18 TCR-α chain as well as signaling lymphocytic-activation molecule (SLAM) co-receptor, are positively selected to become stage 0 iNKT cells (CD24+ CD44low NK1.1-). Stage 0 iNKT cells lower their CD24 expression and turn into highly-proliferative stage 1
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