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There is currently a critical need to determine the efficacy of SARS-CoV-2 vaccination for immunocompromised patients. In this study, we determined the neutralizing antibody response in 160 cancer patients diagnosed with chronic lymphocytic leukemia (CLL), lung cancer, breast cancer, and various non-Hodgkin's lymphomas (NHL), after they received two doses of mRNA vaccines. Serum from 46 mRNA vaccinated health care workers (HCWs) served as healthy controls. We discovered that (1) cancer patients exhibited reduced neutralizing antibody titer (NT50) compared to HCWs; (2) CLL and NHL patients exhibited the lowest NT50 levels, with 50-60% of them below the detection limit; (3) mean NT50 levels in patients with CLL and NHL was ~2.6 fold lower than those with solid tumors; and (4) cancer patients who received anti-B cell therapy exhibited significantly reduced NT50 levels. Our results demonstrate an urgent need for novel immunization strategies for cancer patients against SARS-CoV-2, particularly those with hematological cancers and those on anti-B cell therapies. [ABSTRACT FROM AUTHOR]

The transcription factor BATF controls the differentiation of interleukin 17 (IL-17)-producing helper T cells (TH17 cells) by regulating expression of the transcription factor ROR?t itself and ROR?t target genes such as Il17. Here we report the mechanism by which BATF controls in vivo class-switch recombination (CSR). In T cells, BATF directly controlled expression of the transcription factors Bcl-6 and c-Maf, both of which are needed for development of follicular helper T cells (TFH cells). Restoring TFH cell activity to Batf?/? T cells in vivo required coexpression of Bcl-6 and c-Maf. In B cells, BATF directly controlled the expression of both activation-induced cytidine deaminase (AID) and of germline transcripts of the intervening heavy-chain region and constant heavy-chain region (IH-CH). Thus, BATF functions at multiple hierarchical levels in two cell types to globally regulate switched antibody responses in vivo. [ABSTRACT FROM AUTHOR]

Mammals contend with a universe of evolving pathogens by generating an enormous diversity of antigen receptors during lymphocyte development. Precursor or B and T cells assemble functional immunoglobulin (Ig) and T cell receptor (TCR) genes via recombination of numerous variable (V), diversity (D), and joining (J) gene segments. Although this combinatorial process generates significant diversity, genetic reorganization is inherently dangerous. Thus, V(D)J recombination mast be tightly regulated to ensure proper lymphocyte development and avoid chromosomal translocations that cause lymphoid tumors. Each genomic rearrangement is mediated by a common V(D)J recombinase that recognizes sequences flanking all antigen receptor gene segments. The specificity of V(D)J recombination is due, in large part, to changes in the accessibility of chromatin at target gene segments, which either permits or restricts access to recombinase. The chromatin configuration of antigen receptor loci is governed by the concerted action of enhancers and promoters, which function as accessibility control elements (ACEs). In general, ACEs act as conducts for transcription factors, which in turn recruit enzymes that covalently modify or remodel nucleosomes. These ACE-mediated alterations are critical for activation of gene segment transcription and for opening chromatin associated with recombinase target sequences. In this chapter, we describe advances in understanding the mechanisms that control V(D)J recombination at the level of chromatin accessibility. The discussion will focus on cis-acting regulation by ACEs, the nuclear factors that control ACE function, and the epigenetic modifications that establish recombinase accessibility. [ABSTRACT FROM AUTHOR]

Transcription‐coupled disruption of nucleosome cores unlocks DNA substrates for recognition and assembly by V(D)J recombinase. [ABSTRACT FROM AUTHOR]

Summary: The immunoglobulin heavy-chain (IgH) gene locus undergoes radial repositioning within the nucleus and locus contraction in preparation for gene recombination. We demonstrate that IgH locus conformation involves two levels of chromosomal compaction. At the first level, the locus folds into several multilooped domains. One such domain at the 3′ end of the locus requires an enhancer, Eμ; two other domains at the 5′ end are Eμ independent. At the second level, these domains are brought into spatial proximity by Eμ-dependent interactions with specific sites within the VH region. Eμ is also required for radial repositioning of IgH alleles, indicating its essential role in large-scale chromosomal movements in developing lymphocytes. Our observations provide a comprehensive view of the conformation of IgH alleles in pro-B cells and the mechanisms by which it is established. [ABSTRACT FROM AUTHOR]

Summary The genome is organized into topologically associated domains (TADs) that enclose smaller subTADs. Here, we identify and characterize an enhancer that is located in the middle of the V gene region of the immunoglobulin kappa light chain (Igκ) locus that becomes active preceding the stage at which this locus undergoes V(D)J recombination. This enhancer is a hub of long-range chromatin interactions connecting subTADs in the V gene region with the recombination center at the J genes. Deletion of this element results in a highly altered long-range chromatin interaction pattern across the locus and, importantly, affects individual V gene utilization locus-wide. These results indicate the existence of an enhancer-dependent framework in the Igκ locus and further suggest that the composition of the diverse antibody repertoire is regulated in a subTAD-specific manner. This enhancer thus plays a structural role in orchestrating the proper folding of the Igκ locus in preparation for V(D)J recombination. Graphical Abstract Highlights • An enhancer, E88, in the middle of the Igκ locus is a major hub of interactions • Deletion of E88 alters Vκ gene rearrangement frequencies throughout the locus • Structure of the Igκ locus in pro-B cells influences Vκ rearrangement in pre-B cells • V gene rearrangement is likely mediated in a subTAD-specific manner Barajas-Mora et al. demonstrate that an enhancer—E88—in the V gene region of the Igκ locus regulates long-range chromatin interactions, shaping its 3D structure, enabling different V-gene-containing subTADs to come in proximity to the J genes to generate a diverse repertoire. Consequently, E88 deletion perturbs the resulting B cell repertoire. [ABSTRACT FROM AUTHOR]