Immunology

Type I interferons (IFN-I) have long been heralded as key contributors to effective antiviral responses. More widely understood in the context of acute viral infection, the role of this pleiotropic cytokine has been characterized as triggering antiviral states in cells and potentiating adaptive immune responses. Upon induction in the innate immune response, IFN-I triggers the expression of interferon-stimulated genes (ISGs), which upregulate the effector function of immune cells (e.g., dendritic cells, B cells and T cells) towards successful resolution of infections. However, emerging lines of evidence reveal that viral persistence in the course of chronic infections could be driven by deleterious immunomodulatory effects upon sustained IFN-I expression. In this setting, elevation of IFN-I and ISGs is directly correlated to viral persistence and elevated viral loads. It is important to note that the correlation among IFN-I expression, ISGs and viral persistence may be a cause or effect of chronic infection and this is an important distinction to make towards establishing the dichotomous nature of IFN-I responses. The aim of this mini-review is to (i) summarize the interaction between IFN-I and downstream effector responses and therefore (ii) delineate the function of this cytokine on positive and negative immunoregulation in chronic infection. This is a significant consideration given the current therapeutic administration of IFN-I in chronic viral infections whose therapeutic significance is projected to continue despite emergence of increasingly efficacious antiviral regimens. Furthermore, elucidation of the interplay between virus and the antiviral response in the context of IFN-I will elucidate avenues towards more effective therapeutic and prophylactic measures against chronic viral infections.

Natural killer (NK) cells of the innate immune system are cytotoxic lymphocytes that play important roles following transplantation of solid organs and hematopoietic stem cells. Recognition of self HLA class I molecules by inhibitory killer cell immunoglobulin-like receptors (KIR) is involved in the calibration of NK cell effector capacities during a developmental stage, allowing the subsequent recognition and elimination of target cells with decreased expression of self HLA class I (due to virus infection or tumor transformation) or HLA class I disparities (in the setting of allogeneic transplantation). NK cells expressing an inhibitory KIR binding self HLA can be activated when confronted with allografts lacking a ligand for the inhibitory receptor. Following the response of the adaptive immune system, NK cells can further destroy allograft endothelium by antibody-dependent cell-mediated cytotoxicity (ADCC), triggered through cross-linking of the CD16 Fc receptor by donor-specific antibodies bound to allograft. Upon recognizing allogeneic target cells, NK cells also secrete cytokines and chemokines that drive maturation of dendritic cells to promote cellular and humoral adaptive immune responses against the allograft. The cumulative activating and inhibitory signals generated by ligation of the receptors regulates mature NK cell killing of target cells and their production of cytokines and chemokines. This review summarizes the role of NK cells in allograft rejection and proposes mechanistic concepts that indicate a prominent role for KIR-HLA interactions in facilitating NK cells for Fc receptor-mediated ADCC effector function involved in antibody-mediated rejection of solid organ transplants.

Pro-inflammatory cytokines which are generated by immune system cells and mediate many kinds of immune responses are kinds of endogenous polypeptides. They are the effector of the autoimmune system. It is generally accepted that IL-4, IL-6, IL-9, IL-17 and TNF-α are pro-inflammatory cytokines, nonetheless, IL-6 becomes a protagonist among them since it predominately induces pro-inflammatory signaling and regulates massive cellular processes. It has been ascertained that IL-6 is associated with a large number of diseases with inflammatory background, such as autoimmune diseases, anemia of chronic diseases, angiogenesis acute-phase response, bone metabolism, cartilage metabolism and multiple cancers. Despite great progress in the relative field, the targeted regulation of IL-6 response for therapeutic benefits remains incompletely to be understood. It is, therefore, conceivable that understanding mechanisms of IL-6 from the perspective of gene regulation can better facilitate to determine the pathogenesis of the diseases, providing more solid scientific basis for clinical treatment. In this review we summarize the candidate genes that have been implicated in clinical target therapy from the perspective of gene transcription regulation.

Gerlach et al. (2016) demonstrate that CX3CR1 identifies three distinct CD8+ effector
and memory T cell (TMem) subsets. CX3CR1 correlated with the degree of effector differentiation.
Surprisingly, a newly identified CX3CR1int TMem population, not effector memory cells
(CX3CR1hi), was the predominant subset that surveyed non-lymphoid tissues.

The Hippo pathway, known to be tumor suppressive, is surprisingly found to have a
role in suppressing anti-tumor immune responses. Loss of the LATS1/2 kinases results
in the induction of innate and adaptive immune responses that reduce tumor growth
and improves vaccine efficacy.

Dengue virus (DENV) has spread through most tropical and subtropical areas of the world and represents a serious public health problem. The control of DENV infection has not yet been fully successful due to lack of effective therapeutics or vaccines. Nevertheless, a better understanding of the immune responses against DENV infection may reveal new strategies for eliciting and improving antiviral immunity. T cells provide protective immunity against various viral infections by generating effector cells that cooperate to eliminate antigens and memory cells that can survive for long periods with enhanced abilities to control recurring pathogens. Following activation, CD8 T cells can migrate to sites of infection and kill infected cells, whereas CD4 T cells contribute to the elimination of pathogens by trafficking to infected tissues and providing help to innate immune responses, B cells, as well as CD8 T cells. However, it is now evident that CD4 T cells can also perform cytotoxic functions and induce the apoptosis of target cells. Importantly, accumulating studies demonstrate that cytotoxic CD4 T cells develop following DENV infections and may play a crucial role in protecting the host from severe dengue disease. We review our current understanding of the differentiation and function of cytotoxic CD4 T cells, with a focus on DENV infection, and discuss the potential of harnessing these cells for the prevention and treatment of DENV infection and disease.

A major limiting factor in the success of immunotherapy is tumor infiltration by CD8+ T cells, a process that remains poorly understood. In the present study, we characterized homing receptors expressed by human melanoma-specific CD8+ T cells. Our data reveal that P-selectin binding, and expression of the retention integrin, Very Late Antigen (VLA)-1, by vaccine-induced T cells correlate with longer patient survival. Furthermore, we demonstrate that CD8+VLA-1+ tumor-infiltrating lymphocytes (TIL) are highly enriched in melanoma metastases in diverse tissues. VLA-1-expressing TIL frequently coexpress CD69 and CD103, indicating tissue resident memory cell (TRM) differentiation. We employed a mouse model of melanoma to further characterize VLA-1-expressing TIL. Our data show that VLA-1+ TRM develop in murine tumors within 2 weeks, where they exhibit increased activation status, as well as superior effector functions. In addition, in vivo blockade of either VLA-1 or CD103 significantly impaired control of subcutaneous tumors. Together, our data indicate that VLA-1+ TRM develop in tumors and play an important role in tumor immunity, presenting novel targets for the optimization of cancer immunotherapy.