Follicular Helper T cells (TFH) are critical for germinal center (GC) formation. The processes that drive their generation and effector potential remain unclear. Here, we define requirements for MHCII antigen presenting cells (APCs) in murine TFH formation by either transiently ablating or restricting antigen presentation to dendritic cells (DCs). We find that cognate interactions with DCs are necessary and sufficient to prime CD4+ T cells towards a CXCR5+ICOS+Bcl6+ TFH intermediate. However, in the absence of additional APCs, these TFH fail to produce IL-21. Furthermore, in vitro priming of naïve T cells by B cells engenders optimal production of IL-21, which induces a GC B cell transcriptional profile. These results support a multi-step model for effector TFH priming and GC initiation, in which DCs are necessary and sufficient to induce a TFH intermediate that requires additional interactions with distinct APCs for full effector function.

The heterodimeric cytokine interleukin 27 (IL-27) signals through the IL-27Rα subunit combined with gp130, a common receptor chain utilized by several cytokines, including IL-6. Interestingly, the IL-27 subunits p28 and EBI3 are not always co-expressed, suggesting that they may have unique functions. Here, we show IL-27p28, independent of EBI3 antagonized cytokine signaling through gp130 and IL-6 mediated production of IL-17 and IL-10. Similarly, the ability to generate antibody responses was dependent on the activity of gp130-signaling cytokines. IL-27p28 transgenic mice showed a major defect in germinal center formation and antibody production. Thus, IL-27p28, as a natural antagonist of gp130-mediated signaling, may be useful as a therapeutic for managing inflammation mediated by cytokines that signal through gp130.

We have used an inhibiting antibody to determine whether preimmune versus antigen-experienced B cells differ in their requisites for BLyS, a cytokine that controls differentiation and survival. Whereas in vivo BLyS inhibition profoundly reduced naïve B cell numbers and primary immune responses, it had a markedly smaller effect on memory B cells and long-lived plasma cells, as well as secondary immune responses. There was heterogeneity within the memory pools, because IgM-bearing memory cells were sensitive to BLyS depletion whereas IgG-bearing memory cells were not, although both were more resistant than naïve cells. There was also heterogeneity within B1 pools, as splenic but not peritoneal B1 cells were diminished by anti-BLyS treatment, yet the number of natural antibody-secreting cells remained constant. Together, these findings show that memory B cells and natural antibodysecreting cells are BLyS-independent and suggest that these pools can be separately manipulated.

Brucella spp. are intracellular gram-negative bacteria that include a number of virulent species that cause chronic infections in a variety of mammalian hosts. Human infections are proportional to the level of disease in domestic animals because humans are infected zoonotically after contact with infected animals or their products. The chronicity of infection results from the ability of some brucellae to survive reactive oxygen intermediate and nitric oxide killing in host phagocytes, following which they activate bacterial genes in response to the acidic phagosome environment, prevent phagolysosomal fusion by remodeling the intracellular compartment, and subsequently replicate intracellularly. The crucial component of immunity that results in survival of the host and thus maintenance of this chronic infective state is interferon-gamma (IFN-gamma). Production of IFN-gamma results from the ability of brucella components, including lipid A, to interact with Toll-like receptors for the production of IL-12 and TNF-alpha, although the regulatory cytokine IL-10 is also produced and decreases control of the infection. Although CD4 and CD8 T cells are clearly involved in the production of IFN-gamma, and CD8 T cells may be cytotoxic, a role for NK cells and cytotoxicity in protective immunity to brucellosis has not been substantiated experimentally. Moreover, antibodies have been shown to have a limited role in passive transfer studies.

BLyS expression by GC follicular T cells is required for the efficient selection of high-affinity GC B cells.