SALIVARY IGA RESPONSE--REGULATION BY TH1 AND TH2 CELLS

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Secretory IgA (S-IgA) responses in the oral cavity result from antigen stimulation in IgA inductive sites such as the Peyer's patches (PP). Oral immunization induces both T helper (Th) cells which preferentially support IgA responses and IgA committed (surface IgA+; sIgA+) B cells in PP; however, the final stages of IgA responses do not occur in this tissue. Instead, sIgA+ B cells leave PP following antigen stimulation and migrate to distant IgA effector sites including the salivary glands (SG) as well as the lamina propria (LP) regions of the intestinal, bronchus and genitourinary tracts, where S-IgA antibody responses occur. Our studies have shown that murine PP Th cells, which preferentially support IgA responses, produce IL-5 and IL-6 which suggest their classification as Th2 type. The PP also contain Th1 cells (producing IFNgamma and IL-2); which is similar to those Th cell types from spleen. However, Th2-type cells in spleen support IgM and IgG, but not IgA responses. On the other hand, IgA effector sites, e.g., the LP of the small intestine, contained a higher frequency of IL-5 and IL-6 producing Th2 cells. From these studies, we postulate that Th2 cells in IgA inductive and effector sites differ from those obtained from systemic tissue, although both types produce IL-4, IL-5 and IL-6. In this grant, we will determine if Th2 cells for IgA responses occur in SG and if they originate from Th2 cell precursors in PP. These studies will also include the characterization of the T cell receptor, e.g., gammadelta versus alphabeta used by SG T cells. Thus, the frequency of TCR1 (gammadelta) and TCR2 (alphabeta) bearing T cells will be examined by mAb UC7-13D5 and H57.597, respectively, in different subsets of SG T cells including CD4+ or CD8+ or CD4-, CD8-fractions. Since TCR1+ T cells from different tissues use different Vgamma gene segments (e.g., Vgamma6 for tongue and Vgamma7 for intraepithelial lymphocytes), the major family of Vgamma gene segments for SG TCR1+ T cells will be elucidated. This proposal will also address whether Th1 and Th2 cells which reside in SG produce a distinct pattern of cytokines by cytokine-specific ELISPOT and mRNA-cDNA hybridization using freshly isolated T cells and antigen-specific T cell clones from SG. To identify Th1- or Th2-type cytokine producing cells in SG at the single cell level, cytokine-specific in situ hybridization will be employed. We will directly address why Th2 cells for IgA responses develop in the PP and SG, and the mechanism(s) responsible for their induction. For this purpose, SCID mice will be reconstituted by PP CD4+ T cells or antigen-specific T cell clones. Further, possible involvement of antigen-presenting cells in PP and SG, and neuropeptides and hormones for the induction of unique subsets of Th2 cells in SG will be studied. Finally, we will determine the Th2-B cell interactions and cytokine requirements for terminal differentiation of B cells into plasma cells in the SG. These studies will establish at the cellular and molecular levels, how T cells regulate salivary S-IgA response.