Citations

Abstract Optimum function of HLA-DR molecules in transgenic mice requires efficient interaction between the class II molecules on APCs and CD4 on T cells. Residues 110 and 139 of the second domain of class II molecules are considered to be critical for recognition of CD4. We generated an HLA-DR4β(NT) transgene construct in which positions 110 and 139 were altered to resemble endogenous mouse H2 Aβ molecules. This construct was introduced into (B10 × SWR) embryos, and DR4β(NT) transgenic mice were produced. The transgene was transferred into B10.RFB3 (Eβ0 Eαp) mice. The transgene-encoded DR4β molecules paired with endogenous Eα chains to form stable DR4β/Eα dimers expressed on the cell surface. The hybrid dimers showed similar Ag-binding specificity to HLA-DR4 molecules and positively selected CD4+ T cells in vivo. Immunization of HLA-DR4β(NT) transgenic mice with DR4-restricted peptides induced T cell proliferation in vitro. While the purified T cells from DR4β(NT) transgenic mice responded strongly to the HA(307–319) presented by M12C3 transfectants expressing altered DR4β/Eα heterodimers, the response to the same peptides presented by transfectants expressing wild-type DR4β/Eα molecules was substantially reduced. Taken together, these data confirmed in vitro studies on the importance of these residues in CD4-MHC class II interaction. The altered HLA-DR4β transgenic mice were able to overcome the species barrier and generate efficient HLA-DR4-restricted CD4-specific immune responses. Thus, residues 110 and 139 were critical for the interaction of class II with CD4 T cells during thymic selection as well as peripheral immune responses.

The Drosophila immune deficiency (IMD) pathway, homologous to the mammalian tumor necrosis factor (TNF‐α) signaling pathway, initiates antimicrobial peptide (AMP) production in response to infection by gram‐negative bacteria. A membrane‐spanning peptidoglycan recognition protein, PGRP‐LC, functions as the receptor for the IMD pathway. This receptor is activated via pattern recognition and binding of monomeric peptidoglycan (DAP‐type PGN) through the PGRP ectodomain. In this article, we show that the receptor PGRP‐LC is down‐regulated in response to Salmonella/Escherichia coli infection but is not affected by Staphylococcus infection in vivo, and an ectodomain‐deleted PGRP‐LC lacking the PGRP domain is an active receptor. We show that the receptor PGRP‐LC regulates and integrates two host defense systems: the AMP production and melanization. A working model is proposed in which pathogen invasion and tissue damage may be monitored through the receptor integrity of PGRP‐LC after host and pathogen are engaged via pattern recognition. The irreversible cleavage or down‐regulation of PGRP‐LC may provide an additional cue for the host to distinguish pathogenic microbes from nonpathogenic ones and to subsequently activate multiple host defense systems in Dro‐sophila, thereby effectively combating bacterial infection and initiating tissue repair.—Schmidt, R. L., Trejo, T. R., Plummer, T. B., Platt, J. L., Tang, A. H. Infection‐induced proteolysis of PGRP‐LC controls the IMD activation and melanization cascades in Drosophila. FASEB J . 22, 918–929 (2008)