▪ Abstract Interleukin-4 is a multifunctional cytokine that plays a critical role in the regulation of immune responses. Its effects depend upon binding to and signaling through a receptor complex consisting of the IL-4Rα chain and the common gamma chain (γc), resulting in a series of phosphorylation events mediated by receptor-associated kinases. In turn, these cause the recruitment of mediators of cell growth, of resistance to apoptosis, and of gene activation and differentiation. Here we describe our current understanding of the organization of the IL-4 receptor, of the signaling pathways that are induced as a result of receptor occupancy, and of the various mechanisms through which receptor function is modulated. We particularly emphasize the modular nature of the receptor and the specialization of different receptor regions for distinct functions, most notably the independent regulation of cell growth and gene activation.

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The IL-4 receptor: signaling mechanisms and biologic functions.

The tripartite subdivision of lymphocytes into B cells, αβ T cells, and γδ cells has been conserved seemingly since the emergence of jawed vertebrates, more than 450 million years ago. Yet, while we understand much about B cells and αβ T cells, we lack a compelling explanation for the evolutionary conservation of γδ cells. Such an explanation may soon be forthcoming as advances in unraveling the biochemistry of γδ cell interactions are reconciled with the abnormal phenotypes of γδ-deficient mice and with the striking differences in γδ cell activities in different strains and species. In this review, the properties of γδ cells form a basis for understanding γδ cell interactions with antigens and other cells that in turn form a basis for understanding immunoprotective and regulatory functions of γδ cells in vivo. We conclude by considering which γδ cell functions may be most critical.

[gamma][delta] cells: a right time and a right place for a conserved third way of protection.

Functional subsets of human T cells were delineated by analyzing patterns of lymphokines produced by clones from individuals with leprosy and by T cell clones of known function CD4 clones from individuals with strong cell-mediated immunity produced predominantly interferon-gamma, whereas those clones that enhanced antibody formation produced interleukin-4 CD8 cytotoxic T cells secreted interferon-gamma Interleukin-4 was produced by CD8 T suppressor clones from immunologically unresponsive individuals with leprosy and was found to be necessary for suppression in vitro Both the classic reciprocal relation between antibody formation and cell-mediated immunity and resistance or susceptibility to certain infections may be explained by T cell subsets differing in patterns of lymphokine production

https://science.sciencemag.org/content/sci/254/5029/279.full.pdf

Differing lymphokine profiles of functional subsets of human CD4 and CD8 T cell clones.

γδ T cells are a unique and conserved population of lymphocytes that have been the subject of a recent explosion of interest owing to their essential contributions to many types of immune response and immunopathology But what does the integration of recent and long-established studies really tell us about these cells and their place in immunology? The time is ripe to consider the evidence for their unique and crucial functions We conclude that whereas B cells and αβ T cells are commonly thought to contribute primarily to the antigen-specific effector and memory phases of immunity, γδ T cells are distinct in that they combine conventional adaptive features (inherent in their T cell receptors and pleiotropic effector functions) with rapid, innate-like responses that can place them in the initiation phase of immune reactions This underpins a revised perspective on lymphocyte biology and the regulation of immunogenicity

/pdf/six-of-the-best-unique-contributions-of-gd-t-cells-to-67ypagjcex.pdf

Six-of-the-best: unique contributions of γδ T cells to immunology

Development of functional human blood and immune systems in NOD/SCID/IL2 receptor γ chainnull mice

The association of malignant neoplasms arising contiguous with or adjacent to seborrheic keratoses has been previously documented. In this study a retrospective analysis was performed to further characterize these combined neoplasms. A total of 54 examples of malignant neoplasms in conjunction with seborrheic keratoses were found, of which 43 were basal cell carcinomas, six were Bowen's disease, three were keratoacanthomas, and two were malignant melanomas. The average age of the patients was over 65 years. Men were affected more frequently then women. The posterior thorax was the most common site for malignant neoplasms associated with seborrheic keratoses. The superficial type of basal cell carcinoma was the most common type of basal cell carcinoma found in this association. All subtypes of seborrheic keratosis may be found together with malignant neoplasms. We believe the appellation collision tumor is not valid because it is unknown whether the association of seborrheic keratoses with malignant neoplasms is a random event or whether there is, in fact, a pathogenic relationship in the development of two distinctive neoplasms together. Therefore, the term compound tumor is proposed to designate the finding of two distinctive neoplasms either directly contiguous with each other or immediately adjacent to each other.

Malignant neoplasms associated with seborrheic keratoses. An analysis of 54 cases.

IFN-gamma receptor deficient (IFN-gamma R-/-) mice, immunized with different developmental stages of malaria parasites, were used to define the mechanisms of protection against the various stages of this infection. IFN-gamma R-/- mice failed to develop protective immunity against Plasmodium yoelii sporozoites or liver stages, upon immunization with a single dose of irradiated sporozoites, whereas in immunized wild-type mice, parasite development was strongly inhibited. Immunized wild-type mice expressed high levels of inducible nitric oxide synthase (iNOS) mRNA in their liver, upon challenge with viable sporozoites, whereas only background levels of iNOS were detected in immunized IFN-gamma R-/- mice. In contrast, after immunization with multiple doses of irradiated sporozoites, both IFN-gamma R-/- and wild-type mice mounted an immune response, which strongly inhibited the development of liver stage parasites. In both types of mice, protection occurred in the absence of appreciable expression of liver iNOS mRNA. As for the course of the erythrocytic phase of infection by nonlethal malaria species, P. yoelii yoelii and P. chabaudi adami, we observed only a moderately prolonged parasitemia in IFN-gamma R-/- mice compared with wild-type mice, indicating that IFN-gamma may only play a modest role in immunity against erythrocytic stages. These results indicate that IFN-gamma is the main mediator of the protective mechanism that develops first upon immunization with sporozoites. However, the nature of the anti-parasite mechanism(s) changes in the course of immunization, so that multiple immunizing doses elicit additional protective mechanisms, which are independent of IFN-gamma and its receptor.

Development of Antimalaria Immunity in Mice Lacking Ifn-Gamma Receptor

The common gamma-chain (gamma(c)) is a functional component of the IL-4R, yet cells lacking gamma(c) are able to respond to IL-4. This has led to the suggestion that a surrogate gamma'-chain, which can interact with the IL-4R alpha chain to mediate signaling, is expressed on cells lacking gamma(c). An alternative possibility is that in the absence of gamma(c), the IL-4R alpha chain is able to transduce signals by homodimerization. To test this latter possibility, a chimeric receptor containing the extracellular domain of c-kit (the stem cell factor (SCF) receptor) and the cytoplasmic and transmembrane domains of the IL-4R alpha chain was generated. Treatment of cells expressing the chimeric receptor kit/IL-4R alpha with SCF induces activation of the IL-4R alpha-associated kinase JAK-1 and the transcription factor STAT6. However, tyrosine phosphorylation of JAK-3, which associates with gamma(c), is not induced by SCF in these cells. SCF-mediated ligation of kit/IL-4R alpha is sufficient to elicit IL-4-specific gene expression, including up-regulation of CD23 and synthesis of germ-line epsilon transcripts. In the T cell line CTLL2, ligation of kit/IL-4R alpha induces cellular proliferation. Finally, in JAK-1-deficient HeLa cells, STAT6 activation by IL-4 is completely abolished. Together, these data demonstrate that the IL-4R alpha cytoplasmic domain is sufficient to activate JAK-1 and STAT6 and to induce expression of IL-4 target genes, thus identifying a mechanism by which IL-4 signaling can proceed in the absence of JAK-3 and gamma(c).

The IL-4 receptor alpha-chain cytoplasmic domain is sufficient for activation of JAK-1 and STAT6 and the induction of IL-4-specific gene expression.

Urticaria and hepatitis C

Tyrosine phosphorylation of STAT6 in response to IL-4 results in the formation of STAT6 homodimers that bind specific DNA elements. Although binding sites for STAT6 have been shown to be important for the function of several IL-4-inducible promoters, the role of STAT6 in this activation has not been defined. To determine whether STAT6 is a transcriptional activator, different portions of the carboxyl terminus of STAT6 were fused to the yeast Gal4 protein DNA binding domain. Analysis of these chimeric Gal4-STAT6 proteins demonstrates that a 140-amino-acid proline-rich region of the carboxyl terminus of STAT6 contains a region that activates transcription. Truncation mutants of STAT6 that lack this domain cannot activate transcription and are capable of repressing transcription stimulated by a wild-type STAT6 protein. Strikingly, the ability of IL-4 to induce transcription from the Ig germline epsilon promoter is suppressed by overexpression of a carboxyl-terminal deletion mutant of STAT6. These studies demonstrate that the carboxyl terminus of STAT6 contains an activating domain required for the induction of genes by IL-4.

Martin Reichel

Papers

Malignant neoplasms associated with seborrheic keratoses. An analysis of 54 cases.

Development of Antimalaria Immunity in Mice Lacking Ifn-Gamma Receptor

The IL-4 receptor alpha-chain cytoplasmic domain is sufficient for activation of JAK-1 and STAT6 and the induction of IL-4-specific gene expression.

Urticaria and hepatitis C

Identification of a STAT6 domain required for IL-4-induced activation of transcription.