T cell subsets and their signature cytokines in autoimmune and inflammatory diseases

Research over the last 7 years has led to the formal identification of innate lymphoid cells (ILCs), increased the understanding of their tissue distribution and has established essential functions of ILCs in diverse physiological processes. These include resistance to pathogens, the regulation of autoimmune inflammation, tissue remodeling, cancer and metabolic homeostasis. Notably, many ILC functions appear to be regulated by mechanisms distinct from those of other innate and adaptive immune cells. In this Review, we focus on how group 2 ILC (ILC2) and group 3 ILC (ILC3) responses are regulated and how these cells interact with other immune and non-immune cells to mediate their functions. We highlight experimental evidence from mouse models and patient-based studies that have elucidated the effects of ILCs on the maintenance of tissue homeostasis and the consequences for health and disease.

Innate lymphoid cells as regulators of immunity, inflammation and tissue homeostasis

Kinases of the Jak ('Janus kinase') family and transcription factors (TFs) of the STAT ('signal transducer and activator of transcription') family constitute a rapid membrane-to-nucleus signaling module that affects every aspect of the mammalian immune system. Research on this paradigmatic pathway has experienced breakneck growth in the quarter century since its discovery and has yielded a stream of basic and clinical insights that have profoundly influenced modern understanding of human health and disease, exemplified by the bench-to-bedside success of Jak inhibitors ('jakinibs') and pathway-targeting drugs. Here we review recent advances in Jak-STAT biology, focusing on immune cell function, disease etiology and therapeutic intervention, as well as broader principles of gene regulation and signal-dependent TFs.

Mechanisms and consequences of Jak–STAT signaling in the immune system

These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer-reviewed by leading experts in the field, making this an essential research companion.

Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)

Interleukin-22 (IL-22) is a recently described IL-10 family cytokine that is produced by T helper (Th) 17 cells, γδ T cells, NKT cells, and newly described innate lymphoid cells (ILCs). Knowledge of IL-22 biology has evolved rapidly since its discovery in 2000, and a role for IL-22 has been identified in numerous tissues, including the intestines, lung, liver, kidney, thymus, pancreas, and skin. IL-22 primarily targets nonhematopoietic epithelial and stromal cells, where it can promote proliferation and play a role in tissue regeneration. In addition, IL-22 regulates host defense at barrier surfaces. However, IL-22 has also been linked to several conditions involving inflammatory tissue pathology. In this review, we assess the current understanding of this cytokine, including its physiologic and pathologic effects on epithelial cell function.

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Interleukin-22: Immunobiology and Pathology

Treg-mediated suppression of conventional T cells is a fundamental step in regulating the adaptive immune response. It is known that Treg first appeared in vertebrates. However, little is known about the of major suppression pathways mediated by Tregs. We employed artificial intelligence text mining system to highlight the suppression pathways currently known to be utilized by Tregs. Our system identified various pathways mediated by CTLA4, calcium signaling, NfkB and NFAT. We simultaneously employed detailed phylogenetic analysis including multiple sequence alignment, phylogenetic tree building, ancestral sequence reconstruction, neutrality tests and positive selection test to investigate the evolution of Treg mediated pathways. We found that CTLA4 first appeared in vertebrates possibly arising from an IGV containing protein in cartilaginous fish. Conversely, we found that Tregs repurposed ancient pathways such as Calcineurin and CAMP Response Element Modulator. Interestingly, these two pathways were highly conserved between vertebrates and lower invertebrates indicating conservation of function. Taken together, our research indicate that Tregs evolved its regulatory systems that evolved in vertebrates as well as reused conserved ancient regulatory systems that are related to the innate immune system

/pdf/phylogenetic-analysis-of-molecular-pathways-in-tregs-3uh374yhcd.pdf

Phylogenetic analysis of molecular pathways in Tregs Suppressor Function

A highly conserved membrane protein present in all species of Leishmania can be used as a vaccine antigen for genetic immunization against visceral leishmananiasis.

Dna vaccine as immunoprophylaxis against kala-azar

Visceral leishmaniasis is a protozoal disease caused by the intracellular parasites Leishmania donovani and L.
chagasi/infantum, and it is usually deadly if not treated. To date, no vaccine exists for prophylaxis or immunotherapy,
nor has it been established which effector mechanisms of the immune system are most instrumental
against the parasites. Recent reports have suggested that CD8+ T cells, in addition to CD4+ T cells,
might play major roles in the defense against infection and in the cure of the disease. To identify epitopes
recognized by CD8+ T cells that can be used for immune monitoring to investigate the role of these cells in
human visceral leishmaniasis, as well as in vaccine development, we scanned the entire sequence of the
leishmanial protein kinetoplastid membrane protein (kmp)–11 with overlapping nonapeptides. Thirty peptides
that specifically trigger interferon-g secretion by human CD8+ T cells were identified. Four T cell lines with
specificities for different peptides recognize Leishmania-infected autologous macrophages, which proves that
kmp-11 is processed and presented via the major histocompatibility complex class I pathway of infected cells.
Kmp-11 is thus a candidate antigen for the development of T cell vaccines.

HLA Class I–Restricted T Cell Epitopesof the Kinetoplastid Membrane Protein–11Presented by Leishmania donovani–InfectedHuman Macrophages

The present invention provides a hybrid cell vaccine against Leishmaniasis comprising of syngeneic macrophage with a dominant Leishmania antigen-KMP-11 electrofused with allogenic Dendritic Cell. Hybrid cell vaccination approach with dendritic cells has been widely used successfully in tumor models only. By devising a novel strategy of transfecting syngeneic macrophage cell line from BALB/c mice with a dominant Leishmania antigen-KMP-11 and electrofusing with allogenic DC from C57BLJ6, the inventors obtained a complete clearance of splenic and hepatic parasite burden in late stage L. donovani infection in genetically susceptible BALB/c mice. Curative response resulted from a high KMP-11 specific MHC class I restricted CD8*CTL response. This is the first study that realized the potential of hybrid cell vaccine in the field of infectious disease and clearly shows the contribution of Th2 cytokine response in conferring protection to Leishmania donovani infection in experimental VL model.

Rajatava Basu

Papers

Phylogenetic analysis of molecular pathways in Tregs Suppressor Function

Dna vaccine as immunoprophylaxis against kala-azar

HLA Class I–Restricted T Cell Epitopesof the Kinetoplastid Membrane Protein–11Presented by Leishmania donovani–InfectedHuman Macrophages

A hybrid cell vaccine against leishmaniasis [kala-azar]