Germline configurations of antigen receptor loci in B and T lymphocytes have hundreds of variable (V) region gene-segments, which have the potential to combine with a select few diversity (D) and joining (J) gene-segments to create recombined genes encoding numerous receptors that can recognize a vast repertoire of antigens (6, 7). Given the importance and timing of these events, it is no wonder that the process of “V(D)J recombination” is exquisitely regulated at multiples levels. Two exciting articles, one by Chaumeli and Skok (8) and the other by Choi and Feeney (9), review our current understanding of how transcription factors, chromatin architecture, and the three-dimensional architecture of the nucleus and the topology of genomic DNA regulate this process. An interesting article by Basu and colleagues describes how ubiquitination events regulate the RAG and activation-induced cytidine deaminase (AID) enzymes that are important for recombination (10). Moreover, this article also discusses how these post-translational events also regulate DNA damage at undesirable loci and during cell cycle phases (10).

Recombination and transcription are coupled during hematopoietic development (11–13). The next set of articles deal with factors involved in this coordination. Atchison and colleagues describes the role of an important but ubiquitously expressed transcription factor YY1 in this highly tissue-specific function (14). Clark and colleagues review the function of interleukin-7 receptor (IL7R) and transcription factor STAT5 in balancing proliferation and recombination of the immunoglobulin light chain (Igκ) gene (15). Bergman and colleagues present primary studies on the role of another essential transcription factor Pax5 in regulating the Igκ gene (16). The sequential involvement of transcription factors and chromatin regulators remains an open question, and Choukrallah and Matthias review our current understanding of these factors in B cell development (17). Webb and colleagues discuss the role of transcription factor Bright in both human and mouse B cell development (18), while Serfling and colleagues review the role of NFATc1 transcription factor during hematopoiesis (19).

Because mature B cells encounter a variety of antigens, they undergo both Class-Switch recombination (CSR) and somatic hypermutation (SHM) to diversify their antibody repertoire by utilizing enzymes such as AID. Given that these processes involve DNA breaks, they must be extremely tightly regulated to maintain genomic integrity (20, 21). Kenter and colleagues (22) and Chaudhuri and colleagues (23) present two articles discussing various factors regulating both SHM and CSR, including three-dimensional genomic topology, chromatin, and transcription. Barbara Birshtein discusses the role of the 3′-enhancer in controlling both SHM and CSR, in particular the epigenetic architecture of the enhancer in these processes (24).

The ultimate role of immune cells is to mount an effective adaptive or innate response against pathogens (25). Hence, the transcription factors regulating these responses play an extremely important role. The final three articles deal with the transcription factors involved in immune responses and antigen presentation. Corcoran and colleagues present primary data on the function of transcription factor Oct2 and its co-activator Obf1/OCA-B in collaboration between B and T cells during an adaptive immune response (26). Bhatt and Ghosh discuss the role of the critical transcription factor NF-kB in innate immune response and how it controls the process of inflammation, which is crucial in maintaining immune homeostasis (27). Finally, Devaiah and Singer discuss our current understanding of the role of Class II transactivator CIITA (28), which is a master regulator of major histocompatibility complex gene expression necessary for antigen presentation (29).

Mechanisms that regulate communication between enhancers and promoters are complex and involve many transcription factors, accessory molecules and chromatin regulators (30). Given the exquisite timing and precision that are necessary to mount an effective immune response, it is fully anticipated that such complex regulatory mechanisms must be in full display for this to occur. The next few years will undoubtedly uncover more surprises that ultimately will lead to a better understanding of the role of transcription in immune responses.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.