The hemopoietic specific adapter protein ADAP (adhesion and degranulation-promoting adapter protein) positively regulates TCR-dependent, integrin-mediated adhesion and participates in signaling pathways downstream of the TCR that result in T cell activation. The specific role of ADAP in regulating Ag-dependent T cell interactions with APCs and T cell activation following Ag stimulation is not known. We used ADAP−/− DO11.10 T cells to demonstrate that ADAP promotes T cell conjugation to Ag-laden APCs. Complementary in vitro and in vivo approaches reveal that ADAP controls optimal T cell proliferation, cytokine production, and expression of the prosurvival protein Bcl-xL in response to limiting Ag doses. Furthermore, ADAP is critical for clonal expansion in vivo independent of Ag concentration under conditions of low clonal abundance. These results suggest that ADAP regulates T cell activation by promoting Ag-dependent T cell-APC interactions, resulting in enhanced T cell sensitivity to Ag, and by participating in prosurvival signaling pathways initiated by Ag stimulation.

CCL28 is a recently identified chemokine ligand for CCR10 and CCR3 that has been identified in mucosal epithelial surfaces in diverse tissues. CCL28-mediated eosinophil chemotaxis and peroxidase release were inhibited by preincubation of cells with anti-CCR3. CCL28 was constitutively expressed in lung tissue collected from nonsensitized control mice but increased levels were found in mice sensitized and rechallenged with cockroach antigen (CRA). CCL28 levels peaked in the lungs 24 hours after intratracheal challenge with CRA, whereas eotaxin expression peaked at 8 hours. Increased expression of CCR3 but not CCR10 could be detected during the induction of the CRA-induced pulmonary inflammation. To investigate the role of CCL28 in allergic airway responses, mice were treated with CCL28 antiserum 1 hour before receiving the final CRA challenge. The level of airway hyperresponsiveness in mice treated with anti-CCL28 was significantly reduced at 24 hours, but not 8 hours, compared to mice receiving control serum. This reduction was not related to decreased Th2 cytokine, chemokine, or leukotriene levels at 24 hours although peribronchial eosinophilia was significantly reduced. Thus, CCL28 appears to play a role in regulating eosinophil recruitment to peribronchial regions of the lung possibly by coordinated temporal production with eotaxin.

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The role of PI-3K in leukocyte function has been studied extensively. However, the specific role of the p110gamma isoform of PI- 3K in CD4 T lymphocyte function has yet to be defined explicitly. In this study, we report that although p110gamma does not regulate antigen-dependent CD4 T cell activation and proliferation, it plays a crucial role in regulating CD4 effector T cell migration. Naïve p110gamma(-/-) CD4 lymphocytes are phenotypically identical to their wild-type (WT) counterparts and do not exhibit any defects in TCR-mediated calcium mobilization or Erk activation. In addition, p110gamma-deficient CD4 OT.II T cells become activated and proliferate comparably with WT cells in response to antigen in vivo. Interestingly, however, antigen-experienced, p110gamma-deficient CD4 OT.II lymphocytes exhibit dramatic defects in their ability to traffic to peripheral inflammatory sites in vivo. Although antigen-activated, p110gamma-deficient CD4 T cells express P-selectin ligand, beta2 integrin, beta1 integrin, CCR4, CXCR5, and CCR7 comparably with WT cells, they exhibit impaired F-actin polarization and migration in response to stimulation ex vivo with the CCR4 ligand CCL22. These findings suggest that p110gamma regulates the migration of antigen-experienced effector CD4 T lymphocytes into inflammatory sites during adaptive immune responses in vivo.