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This month's Focus features a series of three specially commissioned Reviews and a Perspective that provide an in-depth analysis of signaling via the T cell antigen receptor and its regulation, as well as the functional consequences of the T cell antigen receptor's recognition of peptides presented on major histocompatibility complex molecules. See http://www.nature.com/ni/focus/TCRsignaling/index.htmlArtwork by Lewis Long depicts a TCR.
TCR ligation activates multiple downstream pathways that lead to myriad functional outputs. Malissen and colleagues discuss how unbiased mass spectrometry using signaling hub 'bait' molecules, such as Lat, provides new insight into TCR signaling cascades.
How agonist peptides initiate the T cell antigen receptor (TCR) signaling cascade is widely debated. Weiss and Chakraborty discuss current models of the proximal signaling events that ensue upon recognition of agonist peptide–MHC complexes by TCRs.
TCR engagement triggers activation of downstream kinases. Navarro and Cantrell discuss how the network of serine/threonine kinases instruct T cell metabolism to participate in immune responses.
Thymocytes and mature T cells are exposed to a broad range of self-peptides of varying reactivity with TCRs. Hogquist and Jameson discuss how differences in self-reactivity and TCR signal strength dictate subsequent cell fates.
A ligand and G protein–coupled receptor activate antimicrobial gene expression in the Caenorhabditis elegans epidermis, in response to wounding and to infection with a fungal pathogen.
AP4, a transcription factor induced by the functionally related transcription factor c-Myc, maintains the cellular metabolic program for the sustained activation and population expansion of CD8+ T cells after the dynamic loss of c-Myc expression.
The unfolded protein response produces modified endogenous RNA substrates for host cytosolic sensors of RNA, which may lead to production of the interferons IFN-α and IFN-β. The accrual of modified RNA is prevented by an RNA nuclease.
The sensors of damage and danger in the nematode epidermis are unclear. Ewbank and colleagues show that the G protein–coupled receptor DCAR-1 detects epithelial damage elicited mechanically or by a fungal pathogen.
RIG-I-like receptors are activated by viral and other foreign RNAs. Stetson and colleagues show that the RNA exosome enzyme SKIV2L prevents RIG-I activation by endogenous RNAs generated by IRE-1 in stressed cells.
Alternatively activated (M2) macrophages use fatty acid oxidation for their metabolic needs. Pearce and colleagues show that triacylglycerols metabolized by lysosomal acid lipase are required for the M2 activation of and function of macrophages.
The factors that drive the differentiation of human follicular helper cells remain largely undefined. Ueno and colleagues show that TGF-β complements STAT3- and STAT4-activating cytokines to promote the initial differentiation of such cells.
Regulatory T (Treg) cells require the cytokine IL-2 for their development. Bishop and colleagues show that the adaptor molecule TRAF3 reduces IL-2 receptor signaling and thereby restrains Treg cell development.
The phosphatase PTPN22 is associated with human autoimmune disease. Zamoyska and colleagues demonstrate that loss of PTPN22 enhances T cell responses to weak agonists and unmasks self-reactivity.
The transcription factor c-Myc is essential for T cell proliferation after priming; however, its expression is transient. Egawa and colleagues show that the transcription factor AP4 is induced by c-Myc and sustains the activation of CD8+ T cells.
T cell development and effector function depends on signaling initiated via the T cell antigen receptor (TCR). Nature Immunologypresents a focus on TCR signaling with four specially commissioned Review and Perspective articles.