Transmembrane Ig & mucin like protein family is closely associated with immune responses. TIM family has 8 members in mice & 3 members in human. TIM-4 is highly expressed on DC & Mϕ. Its receptor, TIM-1, is expressed on activated CD4. TIM-1/TIM-4 interaction costimulates T cell responses. Both TIM-1 & TIM-4 are receptors of Ptdsr, which is the marker of apoptotic cells. Targeting TIM-1/TIM-4 signaling has emerged as a novel strategy in immunoregulation.
a high-affinity a-TIM-1(3B3) has been reported to promotes allograft rejection by augmenting Th1, Th17 & deprogramming Foxp3+Tregs. In contrast, a low affinity a-TIM-1(RMT1-10) prolong GS by increased Tregs& Th2 deviation.
We recently showed, ~7% of naïve B cells express TIM-1. After activation with islet allograft, TIM-1 expression on B cells increased to ~15%. In Bc recipients of B6 islets, a-TIM-1 RMT1-10 treatment increases MST from 12 d to 35d with 30% long-term survival. Wen B cells are depleted by a-CD20, a-TIM-1 accelerate rejection. & a-TIM-1 induced Th2 deviation was also completely dependent on B cells. Also TIM-1 is the specific marker of IL-10+ regulatory B cells. RMT1-10 a-TIM-1induce immunotolerance in allotransplatation through promoting the expansion of IL-10-enriched TIM-1+ Bregs.
Based on the previous findings, we hypothesized that blocking TIM-4, the ligand of TIM-1 with α-TIM-4 probably would also promote GS. As expected, α-TIM-4 treatment alone resulted in long-term survival of isets allografts in all recipients with MST>100d. Interestingly, in α-CD20 induced B-cell depleted recipients , α-TIM-4 was relatively ineffective with a MST 30d. So, a-TIM-4 induced transplantation tolerance also depend on B cells.
cytokine profile analysis reveal that, α-TIM-4 treatment induce Th2 deviation in both CD4 & CD8. While, in B-cell-depleted recipient mice, α-TIM -4 was not effective anymore. So, a-TIM-4 induced Th2 deviation also depend on B cells.
So a-TIM-1 & a-TIM-4 appear similar in transplant models.
In WT mice, they both can induce long-term GS, both induce Th2 deviation.
In B cell deficient mice, both lose long-term GS & lose Th2 deviation.
TIM-1 is expressed on 7% B cells in naive to 30% B cells in a-TIM-1 treated transplanted mice. These cells express low levels of IFN- & high levels of IL-10.
Given the parallel between TIM-1 & TIM-4 in allograft models, We examine TIM-4 expression on B cells.
First we noticed that TIM-4 expressed almost 15% of B cells. However this is a distinct subset from TIM-1+B subset. Very few B