The influence of signals transmitted by the phosphatase calcineurin and the transcription factor NFAT on the development and function of natural killer T (NKT) cells is unclear. In this report, we demonstrate that the transcription factor early growth response 2 (Egr2), a target gene of NFAT, was specifically required for the ontogeny of NKT cells but not that of conventional CD4 + or CD8 + T cells. NKT cells developed normally in the absence of Egr1 or Egr3, which suggests that Egr2 is a specific regulator of NKT cell differentiation. We found that Egr2 was important in the selection, survival and maturation of NKT cells. Our findings emphasize the importance of the calcineurin-NFAT-Egr2 pathway in the development of the NKT lymphocyte lineage.Mouse natural killer T (NKT) cells that express an invariant T cell antigen receptor (TCR) α-chain composed of variable α-chain region 14 (V α 14) and joining α-chain region 18 (J α 18) gene segments (V α 14i) constitute a distinct lymphocyte subset that coexpresses TCRαβ and markers of the NK cell lineage. NKT cells function in the first line of defense against infectious agents, contribute to the development of asthma and chronic obstructive pulmonary disease, potently promote the regression of transplanted tumors, and influence the maintenance of immunological tolerance 1-3 . Unlike conventional T lymphocytes, which express a diverse repertoire of TCRα and TCRβ, NKT cells combine the V α 14i TCRα chain (V α 24-J α 18 in humans) with a restricted repertoire of TCRβ proteins that contain V β 8, V β 7 or V β 2 segments (V β 11 in humans). Also in contrast to conventional T lymphocytes, which recognize peptides bound to major histocompatibility complex molecules and are selected by thymic stromal cells that present complexes of peptide and major histocompatibility complex, NKT cells are

are employees of Genentech, Inc, a member of the Roche group, and own Roche stock. C. E. Brightling is a consultant with fees paid to his institution from Genentech, Inc, and Regeneron; received research grants and was a consultant with fees paid to his institution from AstraZeneca, GlaxoSmithKline, Sanofi, Boehringer Ingelheim, Roche/Genentech, Chiesi, 4D Pharma, Mologics, and Novartis.Background: The IL-33/ST2 pathway is linked with asthma susceptibility. Inhaled allergens, pollutants, and respiratory viruses, which trigger asthma exacerbations, induce release of IL-33, an epithelial-derived ''alarmin.'' Astegolimab, a human IgG 2 mAb, selectively inhibits the IL-33 receptor, ST2. Approved biologic therapies for severe asthma mainly benefit patients with elevated blood eosinophils (type 2-high), but limited options are available for patients with low blood eosinophils (type 2-low). Inhibiting IL-33 signaling may target pathogenic pathways in a wider spectrum of asthmatics. Objectives: This study evaluated astegolimab efficacy and safety in patients with severe asthma. Methods: This double-blind, placebo-controlled, dose-ranging study (ZENYATTA [A Study to Assess the Efficacy and Safety of MSTT1041A in Participants With Uncontrolled Severe Asthma]) randomized 502 adults with severe asthma to subcutaneous placebo or 70-mg, 210-mg, or 490-mg doses of astegolimab every 4 weeks. The primary endpoint was the annualized asthma exacerbation rate (AER) at week 54. Enrollment caps ensured 30 patients who were eosinophil-high (> _300 cells/mL) and 95 patients who were eosinophil-low (<300 cells/mL) per arm. Results: Overall, adjusted AER reductions relative to placebo were 43% (P 5 .005), 22% (P 5 .18), and 37% (P 5 .01) for 490mg, 210-mg, and 70-mg doses of astegolimab, respectively. Adjusted AER reductions for patients who were eosinophil-low were comparable to reductions in the overall population: 54% (P 5 .002), 14% (P 5 .48), and 35% (P 5 .05) for 490-mg, 210mg, and 70-mg doses of astegolimab. Adverse events were similar in astegolimab-and placebo-treated groups. Conclusions: Astegolimab reduced AER in a broad population of patients, including those who were eosinophil-low, with inadequately controlled, severe asthma. Astegolimab was safe and well tolerated. (J Allergy Clin Immunol 2021;nnn:nnnnnn.)

Hepatic infiltration of activated CD8 lymphocytes is a major feature of graft-vs-host disease (GvHD). Chemoattractant cytokines and their receptors are key regulators of lymphocyte trafficking, but the involvement of chemoattractant receptors in the physiologic recruitment of cells into the inflamed liver has not been defined. The present study examines the role of the chemokine receptor CXCR6, which is highly expressed by liver-infiltrating CD8 T cells. Hepatic accumulation of donor CD8, but not donor CD4, lymphocytes was significantly reduced in GvHD induced by transfer of CXCR6−/−, H-2Db lymphocytes into BDF1, H-2Dbxd recipients. To determine whether altered recruitment contributes to the reduced accumulation, CXCR6−/− or wild-type splenic lymphocytes participating in an active GvHD response were isolated and transferred i.v. into secondary recipients with active GvHD, and the short term (6-h) recruitment of transferred cells to the inflamed liver was assessed. CXCR6−/− CD8 (but not CD4) cells displayed a significant (33%) reduction in liver localization, whereas frequencies in blood of CXCR6−/− and wild-type CD8 cells were similar. Proliferation and apoptosis of liver-infiltrating donor CD8 cells were unaffected. We conclude that CXCR6 helps mediate the recruitment of activated CD8 lymphocytes in GvHD-induced hepatitis and may be a useful target to treat pathological inflammation in the liver.