Autologous dendritic cells prolong allograft survival through Tmem176b-dependent antigen cross-presentation.

The administration of autologous (recipient-derived) tolerogenic dendritic cells (ATDCs) is under clinical evaluation. However, the molecular mechanisms by which these cells prolong graft survival in a donor-specific manner is unknown. Here, we tested mouse ATDCs for their therapeutic potential in a skin transplantation model. ATDC injection in combination with anti-CD3 treatment induced the accumulation of CD8(+) CD11c(+) T cells and significantly prolonged allograft survival. TMEM176B is an intracellular protein expressed in ATDCs and initially identified in allograft tolerance. We show that Tmem176b(-/-) ATDCs completely failed to trigger both phenomena but recovered their effect when loaded with donor peptides before injection. These results strongly suggested that ATDCs require TMEM176B to cross-present antigens in a tolerogenic fashion. In agreement with this, Tmem176b(-/-) ATDCs specifically failed to cross-present male antigens or ovalbumin to CD8(+) T cells. Finally, we observed that a Tmem176b-dependent cation current controls phagosomal pH, a critical parameter in cross-presentation. Thus, ATDCs require TMEM176B to cross-present donor antigens to induce donor-specific CD8(+) CD11c(+) T cells with regulatory properties and prolong graft survival.

Copy number variation in chemokine superfamily: the complex scene of CCL3L-CCL4L genes in health and disease.

Genome copy number changes (copy number variations: CNVs) include inherited, de novo and somatically acquired deviations from a diploid state within a particular chromosomal segment. CNVs are frequent in higher eukaryotes and associated with a substantial portion of inherited and acquired risk for various human diseases. CNVs are distributed widely in the genomes of apparently healthy individuals and thus constitute significant amounts of population-based genomic variation. Human CNV loci are enriched for immune genes and one of the most striking examples of CNV in humans involves a genomic region containing the chemokine genes CCL3L and CCL4L. The CCL3L-CCL4L copy number variable region (CNVR) shows extensive architectural complexity, with smaller CNVs within the larger ones and with interindividual variation in breakpoints. Furthermore, the individual genes embedded in this CNVR account for an additional level of genetic and mRNA complexity: CCL4L1 and CCL4L2 have identical exonic sequences but produce a different pattern of mRNAs. CCL3L2 was considered previously as a CCL3L1 pseudogene, but is actually transcribed. Since 2005, CCL3L-CCL4L CNV has been associated extensively with various human immunodeficiency virus-related outcomes, but some recent studies called these associations into question. This controversy may be due in part to the differences in alternative methods for quantifying gene copy number and differentiating the individual genes. This review summarizes and discusses the current knowledge about CCL3L-CCL4L CNV and points out that elucidating their complete phenotypic impact requires dissecting the combinatorial genomic complexity posed by various proportions of distinct CCL3L and CCL4L genes among individuals.