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T cells are an essential component of the immune system that provide antigen-specific acute and long lasting immune responses to infections and tumors, ascertain the maintenance of immunological tolerance and, on the flipside, mediate autoimmunity in a variety of diseases. The activation of T cells through antigen recognition by the T cell receptor (TCR) results in transient and sustained Ca 2+ signals that are shaped by the opening of Ca 2+ channels in the plasma membrane and cellular organelles. The dynamic regulation of intracellular Ca 2+ concentrations controls a variety of T cell functions on the timescale of seconds to days after signal initiation. Among the more recently identified roles of Ca 2+ signaling in T cells is the regulation of metabolic pathways that control the function of many T cell subsets. In this review, we discuss how Ca 2+ regulates several metabolic programs in T cells such as the activation of AMPK and the PI3K-AKT-mTORC1 pathway, aerobic glycolysis, mitochondrial metabolism including tricarboxylic acid (TCA) cycle function and oxidative phosphorylation (OXPHOS), as well as lipid metabolism.

Previously we have shown that transcription factor Foxp1 plays an essential role in maintaining naive T cell quiescence; in the absence of Foxp1, mature naive CD8+ T cells proliferate in direct response to homeostatic cytokine IL-7. Here we report that the deletion of Foxp1 in naive CD8+ T cells leads to enhanced activation of PI3K/Akt/mTOR signaling pathway and its downstream cell growth and metabolism targets in response to IL-7. We found that Foxp1 directly regulates Pik3ip1, a negative regulator of PI3K. In addition, we found that deletion of Foxp1 in naive CD8+ T cells results in increased expression levels of E2fs, the critical components for cell cycle progression and proliferation, in a manner that is not associated with increased phosphorylation of retinoblastoma protein (Rb). Taken together, our studies suggest that Foxp1 enforces naive CD8+ T cell quiescence by simultaneously repressing key pathways in both cellular metabolism and cell cycle progression.

Understanding the mechanisms that lead to autoimmunity is critical for defining potential therapeutic pathways. In this regard there have been considerable efforts in investigating the interacting roles of TGF-β and IL-2 on the function regulatory T cells. We have taken advantage of dnTGF-βRII Il2ra−/− (abbreviated as Il2ra−/−Tg) mouse model, which allows a direct mechanistic approach to define the relative roles of TGF-β and IL-2 on Treg development. Il2ra−/−Tg mice spontaneously developed multi-organ autoimmune diseases with expansion of pathogenic T cells and enhanced germinal center response at 3–4 weeks of age. Importantly, peripheral Treg cells from Il2ra−/−Tg mice demonstrated an activated Th1-like stable phenotype and normal in vitro suppressive function, while thymus Treg increased but manifested decreased suppressive function. Interestingly, neither thymus nor peripheral Treg cells of Il2ra−/−Tg mice contained Neuropilin-1+ or PD-1hi phenotype, resulting in defective follicular regulatory T (Tfr) cell development. Such defective Tfr development led to elevated follicular T helper cells, enhanced germinal center responses and increased plasma cell infiltration. These data demonstrate an important synergetic role of TGF-β and IL-2 in the generation, activation and stability of Treg cells, as well as their subsequent development into Tfr cells.

T follicular helper (Tfh) cells are essential for germinal center B cell responses. The molecular mechanism underlying the initial Tfh cell differentiation, however, is still incompletely understood. In this study, we show that in vivo, despite enhanced non–Tfh cell effector functions, the deletion of transcription factor Bach2 results in preferential Tfh cell differentiation. Mechanistically, the deletion of Bach2 leads to the induction of CXCR5 expression even before the upregulation of Ascl2. Subsequently, we have identified a novel regulatory element in the murine CXCR5 locus that negatively regulates CXCR5 promoter activities in a Bach2-dependent manner. Bach2 deficiency eventually results in a collapsed CD4+ T cell response with severely impaired CD4+ T cell memory, including Tfh cell memory. Our results demonstrate that Bach2 critically regulates Tfh cell differentiation and CD4+ T cell memory.

T follicular helper (Tfh) cells play an essential role in the formation of germinal centers (GC) and generation of high-affinity Abs. The homing of activated CD4 T cells into B cell follicles and the involvement of key costimulatory and coinhibitory molecules are critical in controlling both the initiation and the magnitude of GC responses. Meanwhile, studies have shown that a high number of single clone B cells leads to intraclonal competition, which inhibits the generation of high-affinity Abs. Our previous work has shown that transcription factor Foxp1 is a critical negative regulator of Tfh cell differentiation. In this study, we report that the deletion of Foxp1 leads to a high proportion of activated CD4 T cells homing into B cell follicles with faster kinetics, resulting in earlier GC formation. In addition, we show that Foxp1-deficient Tfh cells restore the generation of high-affinity Abs when cotransferred with high numbers of single clone B cells. We find that Foxp1 regulates the expression levels of cytotoxic T lymphocyte-associated Ag-4 (CTLA-4) in activated CD4 T cells and that is a direct Foxp1 target. Finally, we demonstrate that CTLA-4 expression on conventional CD4 T cells plays a cell-intrinsic role in Tfh cell differentiation in vivo, and CTLA-4 blockade helps abolish the intraclonal competition of B cells in generating high-affinity Abs.

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A comparative study was conducted to evaluate the chiral recognition ability of several inherently chiral calixcrown carboxylic acids towards chiral aminoalcohols. 1 H NMR titration experiments indicated that inherently chiral calixcrown carboxylic acids each having a phenolic hydroxyl group possess superior chiral recognition ability to the completely alkylated calixarene derivatives. Particularly, inherently chiral calix[4]crown-6 carboxylic acid cone conformer 10 demonstrated significant enantioselectivity in its chiral recognition towards 2-amino-3-methyl-1-butanol (G3) and 2-amino-2-phenylethanol (G6), with the (cS)-10 preferably binding the (S)-guests. Job plots confirmed that 10 and both enantiomers of G3/ G6 form 1 : 1 instantaneous complexes. DFT calculations revealed the existence of multiple hydrogen bonds in the host-guest complexes. The enantioselectivity of the recognition is ascribed to the stronger hydrogen bonding between (cS)-10 and (S)-guests than between (cS)-10 and (R)-guests, based on the calculation results.