Recent data illustrate a key role for the transcriptional regulator bric-a-brac, tramtrack, and broad complex and cap’n’collar homology (Bach)2 in orchestrating T cell differentiation and function. Although Bach2 has a well-described role in B cell differentiation, emerging data show that Bach2 is a prototypical member of a novel class of transcription factors that regulates transcriptional activity in T cells at super-enhancers, or regions of high transcriptional activity. Accumulating data demonstrate specific roles for Bach2 in favoring regulatory T cell generation, restraining effector T cell differentiation, and potentiating memory T cell development. Evidence suggests that Bach2 regulates various facets of T cell function by repressing other key transcriptional regulators such as B lymphocyte–induced maturation protein 1. In this review, we examine our present understanding of the role of Bach2 in T cell function and highlight the growing evidence that this transcriptional repressor functions as a key regulator involved in maintenance of T cell quiescence, T cell subset differentiation, and memory T cell generation.

Summary: Specific interaction of class II/peptide with the T‐cell receptor (TCR) expressed by class II‐restricted CD4⁺ T helper (Th) cells is essential for in vivo production of antibodies reactive with T‐dependent antigen. In response to stimulation with CD1d‐binding glycolipid, Vα14⁺ TCR‐expressing, CD1d‐restricted natural killer T (NKT) cells may provide additional help for antibody production. We tested the hypothesis that the CD1d‐binding glycolipid α‐galactosylceramide (α‐GC) enhances production of antibodies reactive with T‐dependent antigen in vivo. α‐GC enhanced antibody production in vivo in a CD1d‐dependent manner in the presence of class II‐restricted Th cells and induced a limited antibody response in Th‐deficient mice. α‐GC also led to alterations in isotype switch, selectively increasing production of immunoglobulin G2b. Further analysis revealed that α‐GC led to priming of class II‐restricted Th cells in vivo. Additionally, we observed that α‐GC enhanced production of antibodies reactive with T‐independent antigen, showing the effects of NKT cells on B cells independently of Th cells. Our data show that NKT cells have multiple effects on the induction of a humoral immune response. We propose that NKT cells could be exploited for the development of novel vaccines where protective antibody is required.

NKT cell activation with CD1d‐binding glycolipid α‐galactosylceramide (α‐GC) enhances antibody responses to co‐administered T‐dependent antigen. The efficacy of α‐GC relative to other CD1d‐binding glycolipids and adjuvants is not known. There is little information on how NKT cells affect antibody production beyond initial booster‐stimulated recall responses. We therefore tested the hypothesis that α‐GC stimulates induction of plasma cells and antibody responses as effectively as Th1‐ and Th2‐skewing variants of α‐GC and several other adjuvants. C57BL/6 and CD1d^–/– mice were immunized with nitrophenol‐conjugated keyhole limpet hemocyanin (NP‐KLH) plus α‐GC or NP‐KLH plus adjuvants before administration of an NP‐KLH booster and assessing antibody responses and plasma cell frequency. α‐GC boosted long‐term antibody responses as efficiently as all other agents tested and induced plasma cells that were detected in bone marrow 13 weeks after immunization. We then determined whether NKT cells were required in the presence of other adjuvants. CD1d^–/– mice had a reduced induction of plasma cells in response to NP‐KLH/Alum as compared to C57BL/6 mice. However, NKT cells were not required for the continued presence of those cells that were induced. Although NKT cells are capable of inducing persistent plasma cell responses, they may not play a major role in supporting longevity post‐induction.

CD1d-restricted invariant NKT (iNKT) cells boost humoral immunity to T-dependent Ags that are coadministered with the CD1d-binding glycolipid Ag α-galactosylceramide (α-GC). Observations that mice lacking iNKT cells have decaying Ab responses following vaccination have led to the hypothesis that iNKT cells express plasma cell (PC) survival factors that sustain specific Ab titers. Bone marrow chimeric mice in which the entire hematopoietic compartment or iNKT cells selectively lacked BAFF, a proliferation-inducing ligand (APRIL), or both BAFF and APRIL were created and immunized with nitrophenol hapten-conjugated keyhole limpet hemocyanin adsorbed to Imject aluminum hydroxide–containing adjuvant or mixed with α-GC. In comparison with BAFF- or APRIL-sufficient bone marrow chimeras, absence of hematopoietic compartment- and iNKT-derived BAFF and APRIL was associated with rapidly decaying Ab titers and reduced PC numbers. The iNKT cell–derived BAFF or APRIL assumed a greater role in PC survival when α-GC was used as the adjuvant for immunization. These results show that iNKT cell–derived BAFF and APRIL each contribute to survival of PCs induced by immunization. This study sheds new light on the mechanisms through which iNKT cells impact humoral immunity and may inform design of vaccines that incorporate glycolipid adjuvants.

(2009). How do natural killer T cells help B cells? Expert Review of Vaccines: Vol. 8, No. 8, pp. 1109-1121.

Exogenous CD1d-binding glycolipid (α-Galactosylceramide, α-GC) stimulates TCR signaling and activation of type-1 natural killer–like T (NKT) cells. Activated NKT cells play a central role in the regulation of adaptive and protective immune responses against pathogens and tumors. In the present study, we tested the effect of Bacillus anthracis lethal toxin (LT) on NKT cells both in vivo and in vitro. LT is a binary toxin known to suppress host immune responses during anthrax disease and intoxicates cells by protective antigen (PA)-mediated intracellular delivery of lethal factor (LF), a potent metalloprotease. We observed that NKT cells expressed anthrax toxin receptors (CMG-2 and TEM-8) and bound more PA than other immune cell types. A sub-lethal dose of LT administered in vivo in C57BL/6 mice decreased expression of the activation receptor NKG2D by NKT cells but not by NK cells. The in vivo administration of LT led to decreased TCR-induced cytokine secretion but did not affect TCR expression. Further analysis revealed LT-dependent inhibition of TCR-stimulated MAP kinase signaling in NKT cells attributable to LT cleavage of the MAP kinase kinase MEK-2. We propose that Bacillus anthracis–derived LT causes a novel form of functional anergy in NKT cells and therefore has potential for contributing to immune evasion by the pathogen. The bacterium Bacillus anthracis is the causative agent of anthrax infection. Anthrax is a life-threatening disease caused by inhalation or ingestion of spores, or transmission through wounds and abrasions. The bacterium secretes toxins, proteins that enter numerous cell types in an infected individual altering their function and contributing to the disease process. Consequently, we and other researchers are dedicated to identifying cells affected by anthrax toxins and to understanding the implications for the function of those cells. We have observed that anthrax toxins adversely affect a type of cell in the immune system known as a natural killer–like T (NKT) cell. NKT cells are found in the bone marrow, blood, spleen, lymph nodes and liver and are required for optimal immune responses. We report that anthrax toxins effectively shut down NKT cells, preventing them from functioning normally. We propose that this has serious consequences because anyone infected with Bacillus anthracis will be less able to mount an immune response against it.