The cytokine interleukin-21 (IL-21) is closely related to IL-2 and IL-15, and their receptors all share the common cytokine receptor gamma chain, gammac, which is mutated in humans with X-linked severe combined immunodeficiency disease (XSCID). We demonstrate that, although mice deficient in the receptor for IL-21 (IL-21R) have normal lymphoid development, after immunization, these animals have higher production of the immunoglobulin IgE, but lower IgG1, than wild-type animals. Mice lacking both IL-4 and IL-21R exhibited a significantly more pronounced phenotype, with dysgammaglobulinemia, characterized primarily by a severely impaired IgG response. Thus, IL-21 has a significant influence on the regulation of B cell function in vivo and cooperates with IL-4. This suggests that these gammac-dependent cytokines may be those whose inactivation is primarily responsible for the B cell defect in humans with XSCID.

Productive interaction of a T lymphocyte with an antigen-presenting cell results in the clustering of the T-cell antigen receptor (TCR) and the recruitment of a large signalling complex to the site of cell-cell contact. Subsequent signal transduction resulting in cytokine gene expression requires the activation of one or more of the multiple isoenzymes of serine/threonine-specific protein kinase C (PKC). Among the several PKC isoenzymes expressed in T cells, PKC-theta is unique in being rapidly recruited to the site of TCR clustering. Here we show that PKC-theta is essential for TCR-mediated T-cell activation, but is dispensable during TCR-dependent thymocyte development. TCR-initiated NF-kappaB activation was absent from PKC-theta(-/-) mature T lymphocytes, but was intact in thymocytes. Activation of NF-kappaB by tumour-necrosis factor alpha and interleukin-1 was unaffected in the mutant mice. Although studies in T-cell lines had suggested that PKC-theta regulates activation of the JNK signalling pathway, induction of JNK was normal in T cells from mutant mice. These results indicate that PKC-theta functions in a unique pathway that links the TCR signalling complex to the activation of NF-kappaB in mature T lymphocytes.

The contributors Christian U. Blank is a medical oncologist and principal investigator at the Netherlands Cancer Institute. He is Professor of Haematology/oncology at the university of Regensburg, Germany, and received an MBA degree from the university of Warwick, UK. His research interests include neoadjuvant immunotherapies, targeted and biological response modifiers, and prognostic markers for cancer immunotherapies. W. Nicholas Haining is a physician-scientist and vice-President for Discovery oncology and Immunology at Merck Research Laboratories. His former academic laboratory at the Dana-Farber Cancer Institute and the Broad Institute focused on understanding the transcriptional control of T cell exhaustion and on identifying regulators of the immune response to cancer in tumour and immune cells. Werner Held's laboratory has a long-standing interest in understanding the development, differentiation and function of natural killer cells and CD8 + T cells. Current work focuses on CD8 + T cell differentiation in response to acute and chronic infections as well as cancer. Patrick G. Hogan's research centres on mechanisms and regulation of cellular calcium signalling, the biology of the nuclear factor of activated T cells (NFAT) family of transcription factors and the transcriptional control of immune cell development and function. Axel Kallies is a professor at the University of Melbourne, Australia. His laboratory studies the molecular control of CD8 + cytotoxic T cell and regulatory T cell differentiation with a focus on populations residing in non-lymphoid tissue, including healthy tissues and tumours. The Kallies laboratory has developed and applied genetic and molecular approaches to this field, including novel gene reporters, metabolic techniques, transcriptional profiling, chromatin immunoprecipitation and accessible chromatin sequencing. Enrico Lugli's laboratory is focused on understanding the biological mechanisms at the basis of memory T cell responses and homeostasis in humans and how this information can be exploited to favour antitumour immune responses in patients with cancer. The group is specialized in single-cell technologies, in particular high-dimensional flow cytometry. Rachel C. Lynn is an associate director of research at Lyell Immunopharma. She received her PhD degree from the the university of Pennsylvania, where she developed multiple preclinical chimeric antigen receptor (CAR) T cell therapy platforms. During her postdoctoral work with Crystal mackall at Stanford university, she developed models to interrogate and strategies to mitigate CAR T cell exhaustion. At Lyell Immunopharma, her research group will continue to investigate optimal strategies for adoptive T cell therapy in cancer.