Regulation of the Immune Response by TGF-β: From Conception to Autoimmunity and Infection

Abstract

Transforming growth factor b (TGF-b) is a pleiotropic cytokine involved in both suppressive and inflammatory immune responses.After 30 years of intense study, we have only begun to elucidate how TGF-b alters immunity under various conditions.Under steady-state conditions, TGF-b regulates thymic T-cell selection and maintains homeostasis of the naı ¨ve T-cell pool.TGF-b inhibits cytotoxic T lymphocyte (CTL), Th1-, and Th2-cell differentiation while promoting peripheral ( p)Treg-, Th17-, Th9-, and Tfh-cell generation, and T-cell tissue residence in response to immune challenges.Similarly, TGF-b controls the proliferation, survival, activation, and differentiation of B cells, as well as the development and functions of innate cells, including natural killer (NK) cells, macrophages, dendritic cells, and granulocytes.Collectively, TGF-b plays a pivotal role in maintaining peripheral tolerance against self-and innocuous antigens, such as food, commensal bacteria, and fetal alloantigens, and in controlling immune responses to pathogens.I n mammals, the innate and adaptive arms of the immune system orchestrate host -defense and inflammatory responses.For example, leukocytes of the myeloid cell lineage use germlineencoded receptors to detect conserved molecular patterns associated with pathogens, which allows them to alert and activate the rest of the immune system, including adaptive immunity.Alternatively, lymphocytes of the adaptive immune system express antigen-specific receptors that distinguish small differences in macromolecules and establish long-term immunity by forming immunological memory.The coupling of these innate and adaptive recognition pathways, and their precise modes of communication provide a robust mechanism that stimulates immunity and protects the host against pathogens.Nevertheless, the immune system tolerates antigens originating from self-, commensal organisms, and the allogeneic fetus.By maintaining this balance between immunity and tolerance, the immune system can promote the physiological well-being of an individual.A pivotal and pleiotropic regulator of immune responses is transforming growth factor b (TGF-b), which was first reported to control 4 These authors contributed equally to this work.