3B). Ku-0059436 chemical structure Taken together these
results indicate that TNF-α gives a costimulatory signal to human T cells and that TNF-α blockade reduces human T cell responses independent of accessory cells. Adoptive T cell transfer is a promising therapeutic strategy in the treatment of malignancies, and to combat virus infections (Ho et al., 2002, June, 2007 and Berger et al., 2009). Such approaches often depend on the efficient in vitro expansion of antigen specific T cells. We used T cell stimulator cells expressing individual costimulatory molecules or combinations thereof to assess their capacity to expand human T cells in vitro. In line with previous data we found that 4-1BB signals enhance the expansion of T cells costimulated via CD28 ( Maus et al., 2002). Furthermore, our results demonstrate that costimulation via CD2 can also potently increase the expansion of human T cells. Stimulator cells co-expressing CD80, CD58 and 4-1BBL induced significantly stronger T cell expansion compared to stimulator cells not expressing CD80. This underlines the importance of CD28 signals and suggests that the combination of CD80, CD58 and 4-1BBL might be especially suited for the expansion of human T cells ( Fig. 4). Importantly, we found that during 5 rounds of stimulation in the presence of these costimulatory
ligands their effector function was retained as the expanded T cells were able to efficiently kill target cells expressing ALK assay anti-CD3 antibodies as surrogate antigen ( Fig. 4D). There are a large number of human molecules that were described to costimulate T cell activation (Leitner et al., 2010). Although for several of these molecules such a role is well established, there are still some ligands where a limited number of studies have addressed their function in T cell stimulation. We have selected
two such molecules, TL1A and CD150, to study their function in T cell activation using our system of stimulator cells (Fig. 5A). For comparison T cell stimulator cells expressing CD58, a member of the CD2 superfamily, and 4-1BBL, a member of the TNF-SF, which are well established costimulatory ligands were also used. TL1A (TNF-like molecule 1A), the newest member of the TNF-superfamily, Sulfite dehydrogenase is described to costimulate murine and human T cell proliferation via interaction with its receptor death receptor 3 (DR3, TRAMP) (Migone et al., 2002, Pappu et al., 2008 and Zhan et al., 2009). In our experiments T cell stimulator cells expressing high levels of anti-CD3 and TL1A strongly enhanced the proliferation of human T cells (Fig. 5B). This costimulatory effect was observed with CD4+ and CD8+ T cells (Fig. 5D). In line with previous studies TL1A stimulation resulted in the induction of IFN-γ (Biener-Ramanujan et al., 2010). In addition, we obtained elevated levels of IL-10 and IL-13 in supernatants of TL1A stimulated T cell cultures (Fig. 5C).
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