| First Author | Thaker YR | Year | 2015 |
| Journal | Immunol Lett | Volume | 163 |
| Issue | 1 | Pages | 113-9 |
| PubMed ID | 25455592 | Mgi Jnum | J:319083 |
| Mgi Id | MGI:6862651 | Doi | 10.1016/j.imlet.2014.10.020 |
| Citation | Thaker YR, et al. (2015) TCR and CD28 activate the transcription factor NF-kappaB in T-cells via distinct adaptor signaling complexes. Immunol Lett 163(1):113-9 |
| abstractText | The transcription factor NF-kappaB is needed for the induction of inflammatory responses in T-cells. Whether its activation by the antigen-receptor and CD28 is mediated by the same or different intracellular signaling pathways has been unclear. Here, using T-cells from various knock-out (Cd28(-/-), adap(-/-)) and knock-in (i.e. Cd28 Y-170F) mice in conjunction with transfected Jurkat T-cells, we show that the TCR and CD28 use distinct pathways to activate NF-kappaB in T-cells. Anti-CD28 ligation alone activated NF-kappaB in primary and Jurkat T-cells as measured by NF-kappaB reporter and EMSA assays. Anti-CD28 also activated NF-kappaB normally in primary T-cells from adap(-/-) mice, while anti-CD3 stimulation required the adaptor ADAP. Over-expression of ADAP or its binding partner SKAP1 failed to enhance anti-CD28 activation of NF-kappaB, while ADAP greatly increased anti-CD3 induced NF-kappaB activity. By contrast, CD28 activation of NF-kappaB depended on GRB-2 binding to CD28 as seen in CD28 deficient Jurkat T-cells reconstituted with the CD28 YMN-FM mutant, and in primary T-cells from CD28 Y170F mutant knock-in mice. CD28 associated with GRB-2, and GRB-2 siRNA impaired CD28 NF-kappaB activation. GRB-2 binding partner and guanine nucleotide exchange factor, VAV1, greatly enhanced anti-CD28 driven activation of NF-kappaB. Further, unlike in the case of anti-CD28, NF-kappaB activation by anti-CD3 and its cooperation with ADAP was strictly dependent on LAT expression. Overall, we provide evidence that CD28 and the TCR complex regulate NF-kappaB via different signaling modules of GRB-2/VAV1 and LAT/ADAP pathways respectively. |
