T Cell–Independent Modulation of Experimental Autoimmune Encephalomyelitis in ADAP-Deficient Mice

Abstract

The adhesion- and degranulation-promoting adaptor protein (ADAP), expressed in T cells, myeloid cells, and platelets, is known to regulate receptor-mediated inside-out signaling leading to integrin activation and adhesion. In this study, we demonstrate that, upon induction of active experimental autoimmune encephalomyelitis (EAE) by immunization with the myelin oligodendrocyte glycoprotein35–55 peptide, ADAP-deficient mice developed a significantly milder clinical course of EAE and showed markedly less inflammatory infiltrates in the CNS than wild-type mice. Moreover, ADAP-deficient recipients failed to induce EAE after adoptive transfer of myelin oligodendrocyte glycoprotein–specific TCR-transgenic T cells (2D2 T cells). In addition, ex vivo fully activated 2D2 T cells induced significantly less severe EAE in ADAP-deficient recipients. The ameliorated disease in the absence of ADAP was not due to expansion or deletion of a particular T cell subset but rather because of a strong reduction of all inflammatory leukocyte populations invading the CNS. Monitoring the adoptively transferred 2D2 T cells over time demonstrated that they accumulated within the lymph nodes of ADAP-deficient hosts. Importantly, transfer of complete wild-type bone marrow or even bone marrow of 2D2 TCR–transgenic mice was unable to reconstitute EAE in the ADAP-deficient animals, indicating that the milder EAE was dependent on (a) radio-resistant nonhematopoietic cell population(s). Two-photon microscopy of lymph node explants revealed that adoptively transferred lymphocytes accumulated at lymphatic vessels in the lymph nodes of ADAP-deficient mice. Thus, our data identify a T cell–independent mechanism of EAE modulation in ADAP-deficient mice.

LRCH1 interferes with DOCK8-Cdc42–induced T cell migration and ameliorates experimental autoimmune encephalomyelitis

“…1 A, left). In agreement with our observation, previous studies suggest that a deficiency of VAV1 or ADAP ameliorates myelin oligodendrocyte glycoprotein peptide (MOG 35–55)–induced EAE, a mouse model that mimics human MS (Korn et al, 2003; Engelmann et al, 2013). Because Mst1 binds to the RapL–Rap1 complex, whereas DOCK8 is the key downstream effector of Mst1 (Mou et al, 2012), we asked whether DOCK8 influenced the pathogenesis of MS/EAE.…”

Characterization of Mice with a Platelet-Specific Deletion of the Adapter Molecule ADAP

“…We have previously shown that conventional ADAP k.o. mice develop much milder EAE than wild-type mice, however, most likely mainly due to a T cell-independent mechanism (25). Therefore, on the basis of our observed effects of specific ADAP k.o.…”

“…The induction of EAE in ADAP-deficient recipient mice reconstituted with wild-type bone marrow also revealed milder EAE, suggesting a mainly T cell-independent mechanism. These data indicated possible effects of radioresistant cells or indirect effects of other hematopoietic cells (25).…”

ADAP plays a pivotal role in CD4+ T cell activation but is only marginally involved in CD8+ T cell activation, differentiation, and immunity to pathogens

“…In animal models of heart and intestinal allograft transplantations, ADAP deficiency improved the survival of the grafts significantly, emphasizing the crucial role of ADAP in the induction of T cell-mediated immunity [19,20]. Moreover, we have demonstrated that ADAP deficiency ameliorates experimental autoimmune encephalomyelitis in mice, a model strongly relying on CD4 + T cells, although surprisingly, not in a T cell-intrinsic manner [21]. Interestingly, a recent finding also suggests a more regulatory role for ADAP.…”