Transplantation of xenogeneic thymus tissue allows xenograft tolerance induction in the highly disparate pig-to-mouse model. Fetal swine thymus (SW THY) can support generation of a diverse human T cell repertoire that is tolerant of the pig in vitro. We demonstrate here that SW THY generates all human T cell subsets, including Tregs, in similar numbers as human thymus (HU THY) grafts in immunodeficient mice receiving the same human CD34+ cells. Peripheral T cells are specifically tolerant to the mouse and to the human and porcine donors, with robust responses to non-donor human and pig antigens. Specific tolerance is observed to pig skin grafts sharing the THY donor MHC. SW THY-generated peripheral Tregs show similar function, but include lower percentages of naïve-type Tregs compared to HU THY-genereated Tregs. Tregs contribute to donor-pig specific tolerance. Peripheral human T cells generated in SW THY exhibit reduced proportions of CD8+ T cells and reduced lymphopenia-driven proliferation and memory-type conversion, accelerated decay of memory-type cells and reduced responses to protein antigens. Thus, SW thymus transplantation is a powerful xenotolerance approach for human T cells. However, immune function may be further enhanced by strategies to permit positive selection by autologous HLA molecules.
Impaired sensitivity to the inhibitory action of n-butyrate in IBD may constitute a determinant in the pathogenesis of these inflammatory diseases.
Complement regulation leads to the generation of complement split products (CSPs) such as complement component (C)4d, a marker for disease activity in autoimmune syndromes or antibody-mediated allograft rejection. However, the physiologic role of C4d has been unknown. By screening murine thymoma BW5147 cells expressing a cDNA library generated from human monocytederived dendritic cells with recombinant human C4d, we identified Ig-like transcript (ILT)4 and ILT5v2 as cellular receptors for C4d. Both receptors, expressed on monocytes, macrophages, and dendritic cells, also interacted with the CSPs C3d, C4b, C3b, and iC3b. However, C4d did not bind to classic complement receptors (CRs). Interaction between cell surface-resident ILT4 and soluble monomeric C4d resulted in endocytosis of C4d. Surprisingly, binding of soluble ILT4 to C4d covalently immobilized to a cellular surface following classic complement activation could not be detected. Remarkably, C4d immobilized to a solid phase via its intrinsic thioester conferred a dose-dependent inhibition of TNF-a and IL-6 secretion in monocytes activated via Fc-cross-linking of up to 50% as compared to baseline. Similarly, C4d conferred an attenuation of intracellular Ca 2+ flux in monocytes activated via Fc-cross-linking. In conclusion, ILT4 represents a scavenger-type endocytotic CR for soluble monomeric C4d, whereas attenuation of monocyte activation by physiologically oriented C4d on a surface appears to be dependent on a yet to be identified C4d receptor.-Hofer, J., Forster, F., Isenman, D. E., Wahrmann, M., Leitner, J., Hölzl, M. A., Kovarik, J. K., Stockinger, H., Böhmig, G. A., Steinberger, P., Zlabinger, G. J. Ig-like transcript 4 as a cellular receptor for soluble complement fragment C4d. FASEB J. 30, 1492-1503 (2016 Complement component C4 plays a key role in both the classic and the lectin pathways of complement activation. It is cleaved by activated C1s or mannan-binding lectin serine protease 2 (MASP2). Activation of C1s from its zymogen form is a consequence of the binding of the C1q moiety of the C1qr 2 s 2 complex to the Fc arrays of immune complexes (ICs), to apoptotic cellular material or to pathogen surfaces. Similarly, zymogen MASP2 exists in complex with mannosebinding lectin or ficolins and becomes activated when mannose-binding lectin or ficolins bind to terminal mannoses or acetylated entities on invading pathogens. C4 cleavage by C1s or MASP2 results in the exposure of a highly reactive intrinsic thioester, which either immediately hydrolyzes through reaction with water in plasma ($95% of activated C4) or reacts with target antigen resulting in the formation of covalent amide or ester bonds [#5% of activated C4 (1)]. Although the latter reaction is pivotal for the generation of the C3 (C4b2a) and the C5 (C4b2a3b) convertases of the classic and lectin pathways of complement activation, the former reaction results in considerable amounts of inactivated C4b that has to be cleared from the circulation. The thioester of the C3 molecule is equ...
The pancreatic zymogen granule membrane protein (GP2) is expressed by pancreatic acinar cells and M cells of the ileum. GP2 is the closest related homologue of the urine resident Tamm–Horsfall protein (THP). Recently, it was shown that THP is a ligand of various scavenger receptors (SRs). Therefore, we were interested, if GP2 has similar properties.cDNA of different SRs was stably transfected into a murine thymoma cell line. GP2 was recombinantly expressed, purified and biotinylated. Binding or uptake of GP2 by transfected cells or monocyte-derived dendritic cells (moDCs) was analyzed by flow-cytometry.GP2 is a binding partner of the scavenger receptor expressed on endothelial cells I (SREC-I) but not of SR-AI and SR-BI. The dissociation constant (Kd) of GP2 binding to SREC-I is 41.3 nM. SREC transfected cells are able to internalize GP2. moDCs express SREC-I and also bind and internalize GP2. Inhibition of SREC-I on moDCs with anti-SREC-I antibodies does not result in a decreased GP2 binding.Interaction of GP2 with SREC-I and uptake might have profound effects in antigen clearance and mediation of the immune response. In addition to SREC-I other presently unknown receptors for GP2 on DCs might be involved in this process.
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