T cells

T cells are specialized lymphocytes that have vital roles in the immune system. Since their initial description in the 1960s, they have become a major focus of immunology research. In this Nature Milestone on T cells, we explore and celebrate pivotal studies that advanced our understanding of various aspects of T cell biology, including their functions in health and disease and potential for therapeutic application.

Targeting T-cell activation has transformed the therapeutic landscape for patients with immune-mediated diseases. Next-generation treatments will target balance over suppression to achieve their goal.

T cells are often found at the centre of the immune response to many diseases. Scientists who can understand and manipulate them stand a greater chance of creating life-altering treatments.

In this Review, Maria Mittelbrunn and colleagues highlight the involvement of T cells in diseases associated with ageing. In particular, the authors discuss how T cells contribute to inflammageing and the potential of targeting these populations for therapy of age-related diseases.

Alloimmune T cell responses have a crucial role in graft rejection. Here, the authors examine the factors that regulate T cell activation, differentiation and function in secondary lymphoid organs and in the graft, including the different pathways of allorecognition, innate–adaptive immunity crosstalk and the role of survival cytokines.

In this Review, Deborah Fowell and Minsoo Kim highlight the complexity of the biochemical and mechanical cues that facilitate T cell migration. They explain how effector T cells are able to use these cues to navigate through complex tissue environments to respond to pathogens and other immunological challenges.

A high-resolution cryo-electron microscopy structure of the human octameric T cell receptor–CD3 complex, including the complete extracellular and transmembrane domains, reveals the structural basis for TCR–CD3 assembly and provides insights into T cell receptor activation.

γδT cells display potent cytotoxicity towards a large array of haematological and solid tumours while preserving normal tissues. In this Review, Sebestyen et al. analyse the tumour specificity mechanisms of γδT cells and the challenges and opportunities for the use of such cells and their receptors in cancer immunotherapy.

This Review focuses on the roles of γδ T cells in tissue homeostasis and immune surveillance. The authors discuss exciting new studies showing how γδ T cells can regulate diverse physiological responses in tissues, ranging from thermogenesis in adipose tissue to remodelling at neuronal synapses.

The central role of co-stimulatory and co-inhibitory receptors in T cell biology has been proven by the effective therapeutic targeting of some of these molecules. However, the molecular aspects of T cell co-stimulation and co-inhibition are far from being fully understood. Here, the authors discuss emerging concepts in T cell co-signalling.

Immune activating antibodies that target co-stimulatory molecules have altered the cancer therapy landscape. Here, Walker and colleagues discuss therapies — particularly those that target molecules in the same families as CTLA4 and PD1 or TNF receptor — that inhibit the immune system and are being investigated for the treatment of autoimmune diseases. They describe the future opportunities and challenges for the field, including combination approaches.

Recognition of self-peptide–MHC complexes in the thymus is necessary for thymocyte survival, but can also result in cell death. Here, the authors provide a unique insight into this apparent paradox, describing how the repertoire of self-peptide–MHC complexes that support T cell selection is shaped.

Godfrey and colleagues review the basic biology, development, role in disease and immunotherapeutic potential of MAIT cells.

Immunoscore classifies cancers according to their immune infiltration. In this Review, Galon and Bruni provide a panel of therapeutic strategies to use, combine and develop to treat hot, altered and cold tumours.

Although checkpoint inhibitor blockade has been extremely successful in certain types of cancer, harnessing the immune system for immunosurveillance has met with numerous failures. In this Review, Mak and colleagues discuss the lessons learned from these failures, and how to incorporate the growing understanding of immuno-oncology into potential therapies, including combinations with existing checkpoint inhibitors.

The authors compare the thymic development of several innate-like T cell populations, including natural killer T cells, mucosal-associated invariant T cells and γδ T cells. They focus on the cytokines, surface molecules and transcription factors that are necessary for the development of these cells and highlight some of the key differences from conventional T cell development.

T_reg cells have a critical role in maintaining peripheral tolerance. In this Focus Review, Dominguez-Villar and Hafler describe how the instability and plasticity of T_reg cells can contribute to the breakdown of tolerance and lead to autoimmune disease.

In this Viewpoint article, Nature Reviews Immunology invites 18 experts to discuss the nature of T cell exhaustion. How should T cell exhaustion be defined and what are the developmental relationships between exhausted T cell subsets? The contributors share their thoughts on key recent developments in the field.

Chen Dong provides an account of the discovery of T_H17 cells.

The role of T cell help to B cells was discovered only a few years after the discovery of B cells. In this Timeline article, the author describes the key events that led to the identification of T follicular helper (T_FH) cells as the main T helper cell type for B cells.

The widespread clinical translation and commercialization of cell-based therapies are hampered by challenges related to cell source, viability, potency, safety and scalability. Here, Veiseh and colleagues overview progress in the development of cell-based therapeutics and discuss how biological engineering approaches — including genome editing, synthetic biology and the use of biomaterials — are beginning to address key challenges in the field.

Cellular immune responses in rhesus macaques (Macaca mulatta) vaccinated with cytomegalovirus vectors expressing SIV proteins are able to stringently control highly pathogenic SIV infection, regardless of the route of challenge, after systemic spread; immunological and virological analyses of protected macaques followed for up to 3 years suggest that persistent immune surveillance by vaccine-elicited immune responses may have cleared the infection.