Advances in Immunology最新文献

Class switch recombination (CSR) plays an important role in humoral immunity by generating antibodies with different effector functions. CSR to a particular antibody isotype is induced by external stimuli, and occurs between highly repetitive switch (S) sequences. CSR requires transcription across S regions, which generates long non-coding RNAs and secondary structures that promote accessibility of S sequences to activation-induced cytidine deaminase (AID). AID initiates DNA double-strand breaks (DSBs) intermediates that are repaired by general DNA repair pathways. Switch transcription is controlled by various regulatory elements, including enhancers and insulators. The current paradigm posits that transcriptional control of CSR involves long-range chromatin interactions between regulatory elements and chromatin loops-stabilizing factors, which promote alignment of partner S regions in a CSR centre (CSRC) and initiation of CSR. In this review, we focus on the role of IgH transcriptional control elements in CSR and the chromatin-based mechanisms underlying this control.

Over the last decade, the interplay between the gut microbiota, the consortium of intestinal microbes that colonizes intestinal mucosal barriers, and its host immune system has been increasingly better understood. Disruption of the delicate balance between beneficial and pathogenic commensals, known as dysbiosis, contributes to a variety of chronic immunologic and metabolic diseases. Complicating this paradigm are bacterial strains that can operate paradoxically both as instigators and attenuators of inflammatory responses, depending on host background. Here, we review the role of several strains in the genus Lactobacillus within the context of autoimmune and other chronic disorders with a predominant focus on L. reuteri. While strains within this species have been shown to provide immune health benefits, they have also been demonstrated to act as a pathobiont in autoimmune-prone hosts. Beneficial functions in healthy hosts include competing with pathogenic microbes, promoting regulatory T cell development, and protecting the integrity of the gut barrier. On the other hand, certain strains can also break through a dysfunctional gut barrier, colonize internal tissues such as the spleen or liver and promote inflammatory responses in host tissues that lead to autoimmune disease. This review summarizes the manifold roles that these commensals play in the context of health and disease.

CD4 T cells are major immune cell types that mediate effector responses appropriate for diverse incoming threats. These cells have been categorized into different subsets based on how they are induced, expression of specific master transcription factors, and the resulting effector cell phenotypes as defined by expression of signature cytokines. However, recent studies assessing the expression of gene modules in single CD4 T cells, rather than expression of one or a few signature genes, have provided a more complex picture in which the canonical model does not fit as cleanly as proposed. Here, we review the concepts of lineage commitment, plasticity and functional heterogeneity in the context of this greater complexity. We then apply our current understanding of CD4 T cell subsets to discuss outstanding questions regarding follicular helper T cells and follicular regulatory T cells with respect to their shared features with other known CD4 T cell subsets.

Class switch recombination (CSR) generates isotype-switched antibodies with distinct effector functions essential for mediating effective humoral immunity. CSR is catalyzed by activation-induced deaminase (AID) that initiates DNA lesions in the evolutionarily conserved switch (S) regions at the immunoglobulin heavy chain (Igh) locus. AID-initiated DNA lesions are subsequently converted into DNA double stranded breaks (DSBs) in the S regions of Igh locus, repaired by non-homologous end-joining to effect CSR in mammalian B lymphocytes. While molecular mechanisms of CSR are well characterized, it remains less well understood how upstream signaling pathways regulate AID expression and CSR. B lymphocytes express multiple receptors including the B cell antigen receptor (BCR) and co-receptors (e.g., CD40). These receptors may share common signaling pathways or may use distinct signaling elements to regulate CSR. Here, we discuss how signals emanating from different receptors positively or negatively regulate AID expression and CSR.

The vertebrate immune system is tasked with the challenge of responding to any pathogen the organism might encounter, and retaining memory of that pathogen in case of future infection. Recognition and memory of pathogens are encoded within the adaptive immune system and production of T and B lymphocytes with diverse antigen receptor repertoires. In B lymphocytes, diversity is generated by sequential recombination between Variable (V), Diversity (D) and Joining (J) gene segments in the immunoglobulin heavy chain gene (Igh) and subsequent V-J recombination in immunoglobulin light chain genes (Igκ followed by Igλ). However, the process by which particular V, D and J segments are selected during recombination, and stochasticity is maintained to ensure antibody repertoire diversity, is still unclear. In this review, we focus on Igκ and recent findings regarding the relationships between gene structure, the generation of diversity and allelic choice. Surprisingly, the nuclear environment in which each Igκ allele resides, including transcription factories assembled on the nuclear matrix, plays critical roles in both gene regulation and in shaping the diversity of Vκ genes accessible to recombination. These findings provide a new paradigm for understanding Igκ recombination and Vκ diversity in the context of B lymphopoiesis.