Distinct Regulation of Integrin-Dependent T Cell Conjugate Formation and Nf-B Activation by the Adapter Protein Adap

Burbach, B.J.; Srivastava, R.; Medeiros, R.B.; O'Gorman, W.E.; Peterson, E.J.; Shimizu, Y.

The Journal of Immunology 181(7): 4840-4851

2008


DOI: 10.4049/jimmunol.181.7.4840
Accession: 068491177

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Abstract
Following TCR stimulation, T cells utilize the hematopoietic specific adhesion and degranulation-promoting adapter protein (ADAP) to control both integrin adhesive function and NF-kappaB transcription factor activation. We have investigated the molecular basis by which ADAP controls these events in primary murine ADAP(-/-) T cells. Naive DO11.10/ADAP(-/-) T cells show impaired adhesion to OVAp (OVA aa 323-339)-bearing APCs that is restored following reconstitution with wild-type ADAP. Mutational analysis demonstrates that the central proline-rich domain and the C-terminal domain of ADAP are required for rescue of T:APC conjugate formation. The ADAP proline-rich domain is sufficient to bind and stabilize the expression of SKAP55 (Src kinase-associated phosphoprotein of 55 kDa), which is otherwise absent from ADAP(-/-) T cells. Interestingly, forced expression of SKAP55 in the absence of ADAP is insufficient to drive T:APC conjugate formation, demonstrating that both ADAP and SKAP55 are required for optimal LFA-1 function. Additionally, the ADAP proline-rich domain is required for optimal Ag-induced activation of CD69, CD25, and Bcl-x(L), but is not required for assembly of the CARMA1/Bcl10/Malt1 (caspase-recruitment domain (CARD) membrane-associated guanylate kinase (MAGUK) protein 1/B-cell CLL-lymphoma 10/mucosa-associated lymphoid tissue lymphoma translocation protein 1) signaling complex and subsequent TCR-dependent NF-kappaB activity. Our results indicate that ADAP is used downstream of TCR engagement to delineate two distinct molecular programs in which the ADAP/SKAP55 module is required for control of T:APC conjugate formation and functions independently of ADAP/CARMA1-mediated NF-kappaB activation.