Among patients treated with long-acting beta-agonists and medium-to-high doses of inhaled glucocorticoids, those who received tezepelumab had lower rates of clinically significant asthma exacerbations than those who received placebo, independent of baseline blood eosinophil counts. (Funded by MedImmune [a member of the AstraZeneca Group] and Amgen; PATHWAY ClinicalTrials.gov number, NCT02054130 .).

Treatment with AMG 157 reduced allergen-induced bronchoconstriction and indexes of airway inflammation before and after allergen challenge. These findings are consistent with a key role for TSLP in allergen-induced airway responses and persistent airway inflammation in patients with allergic asthma. Whether anti-TSLP therapeutics will have clinical value cannot be determined from these data. (Funded by Amgen; ClinicalTrials.gov number, NCT01405963.).

We have identified the lymphocyte semaphorin CD100/Sema4D as a CD40-inducible molecule by subtractive cDNA cloning. CD100 stimulation significantly enhanced the effects of CD40 on B cell responses. Administration of soluble CD100 markedly accelerated in vivo antigen-specific antibody responses. CD100 receptors with different binding affinities were detected on renal tubular cells (K(d) = approximately 1 x 10(-9)M) and lymphocytes (K(d) = approximately 3 x 10(-7)M). Expression cloning revealed that the CD100 receptor on lymphocytes is CD72, a negative regulator of B cell responsiveness. CD72 thus represents a novel class of semaphorin receptors. CD100 stimulation induced tyrosine dephosphorylation of CD72 and dissociation of SHP-1 from CD72. Our findings indicate that CD100 plays a critical role in immune responses by the novel mechanism of turning off negative signaling by CD72.

The class IV semaphorin CD100/Sema4D differentially utilizes two distinct receptors: plexin-B1 in nonlymphoid tissues, such as brain and kidney, and CD72 in lymphoid tissues. We have generated CD100-deficient mice and demonstrated that they have functional defects in their immune system, without apparent abnormalities in other tissues. The number of CD5(+) B-1 cells was considerably decreased in the mutant mice, whereas conventional B cells and T cells appeared to develop normally. In vitro proliferative responses and immunoglobulin production were reduced in CD100-deficient B cells. The humoral immune response against a T cell-dependent antigen and in vivo priming of T cells were also defective in the mutant mice. These results demonstrate nonredundant and essential roles of CD100-CD72 interactions in the immune system.

IntroductionThe interaction between a T cell and an antigen-presenting cell (APC) is the central event in the induction of an adaptive immune response and involves different and sequential cellular events. Initially, the T cell transiently adheres to the APC and scans its surface for the presence of specific peptide-major histocompatibility (MHC) complexes in an antigen-independent manner. Several receptor-ligand pairs such as CD2/lymphocyte function-associated antigen-3 (LFA-3), LFA-1/intercellular adhesion molecule-1 (ICAM-1) and ICAM-3, and ICAM-3/dendritic cell (DC)-specific ICAM-3-grabbing nonintegrin (DC-SIGN) have been implicated in these early T-cell-APC interactions. 1 In particular, ICAM-1 and -3 play a key role in mediating the initial, antigen-independent adhesion of T cells and APC. 1,2 Once the initial contact has been generated, the contact interface is stabilized by molecular reorganization of antigen receptors, adhesion molecules, costimulatory molecules, and the actin cytoskeleton. This highly organized supramolecular structure is known as the immunological synapse. 3 Adhesion molecules and T-cell-receptor (TCR)-associated components are segregated into 2 major areas within the immunological synapse: the central supramolecular activation cluster (SMAC), which is enriched in TCR/CD3 complexes, costimulatory molecules (CD4, CD2, CD28), and kinases (protein kinase C-[PKC-], Lck, and Fyn), and the peripheral SMAC, including LFA-1 and talin. 4,5 Synapse formation is accompanied by cytoskeletal rearrangements, induction of tyrosine phosphorylation and an increase in intracellular free Ca 2ϩ . Upon Ca 2ϩ mobilization, the nuclear factor of activated T cells (NFAT) is dephosphorylated and translocates to the nucleus, where it acts as a transcriptional regulator of interleukin-2 (IL-2) expression. 6 Activated leukocyte cell adhesion molecule (ALCAM; CD166) is a member of the immunoglobulin (Ig) superfamily of proteins. 7 Although ALCAM is expressed on a wide variety of cells, within the leukocyte population its expression is particularly high on DC. In addition, monocytic cells in synovium from patients with rheumatoid arthritis show strongly increased ALCAM levels compared with resting monocytes, suggesting that ALCAM is involved in regulating immunologic processes such as inflammation. 8 However, the precise role of ALCAM in the immune system is as yet unclear. Similar to several other Ig-like adhesion molecules (NCAM, CEA), ALCAM mediates homotypic ALCAM-ALCAM interactions, 7,9,10 but also heterotypic interactions with the T-cell antigen CD6 have been described. 7 CD6 is a surface receptor expressed by T lymphocytes, thymocytes, and a subset of B cells. [11][12][13] 18 It has been suggested that CD6 fine-tunes CD5 tyrosine phosphorylation by recruiting specific kinases of different families, such as Itk and Lck. 19 CD6 physically associates with the TCR/CD3 complex, it relocalizes upon T-cell activation at the central SMAC (cSMAC) and it modulates immunological synapse maturation in a Jurkat-Raji mo...