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Simple Summary Immune-cell activation is triggered upon antigen or target recognition. This is modulated by co-stimulatory or co-inhibitory signals provided by the cellular environment. The balance between activating and inhibitory receptors controls immune homeostasis, while a disbalance contributes to chronic inflammation and autoimmunity. Binding partners of the Nectin protein family of adhesion molecules are widely expressed in the immune system and are mainly described in cancer immunology. This review summarizes the expression pattern of Nectin binding partners as immune-activating and -inhibitory receptors and how they modulate immune responses in health and autoimmunity. The superfamily of immunoglobulin cell-adhesion molecules (IgCAMs) is a well-known family of cell-adhesion molecules used for immune-cell extravasation and cell-cell interaction. Amongst others, this family includes DNAX accessory molecule 1 (DNAM-1/CD226), class-I-restricted T-cell-associated molecule (CRTAM/CD355), T-cell-activated increased late expression (Tactile/CD96), T-cell immunoreceptor with Ig and ITIM domains (TIGIT), Nectins and Nectin-like molecules (Necls). Besides using these molecules to migrate towards inflammatory sites, their interactions within the immune system can support the immunological synapse with antigen-presenting cells or target cells for cytotoxicity, and trigger diverse effector functions. Although their role is generally described in oncoimmunity, this review emphasizes recent advances in the (dys)function of Nectin-family ligands in health, chronic inflammatory conditions and autoimmune diseases. In addition, this review provides a detailed overview on the expression pattern of Nectins and Necls and their ligands on different immune-cell types by focusing on human cell systems. This work was financially supported by grants from the Research Foundation of Flanders (FWO Vlaanderen), Bijzonder Onderzoeksfonds (BOF) UHasselt and the Belgian Charcot Foundation.

In the original publication, the first and last name of the coauthor "Helga E. de Vries” were incorrectly processed. It is corrected in this correction. The original article has been corrected.

Multiple sclerosis (MS) is a highly debilitating autoimmune disease affecting millions of individuals worldwide. Although classically viewed as T-cell mediated disease, the role of innate lymphoid cells (ILC) such as natural killer (NK) cells and ILC 1-3s has become a focal point as several findings implicate them in the disease pathology. The role of ILCs in MS is still not completely understood as controversial findings have been reported assigning them either a protective or disease-accelerating role. Recent findings in experimental autoimmune encephalomyelitis (EAE) suggest that ILCs infiltrate the central nervous system (CNS), mediate inflammation, and have a disease exacerbating role by influencing the recruitment of autoreactive T-cells. Elucidating the detailed role of ILCs and altered signaling pathways in MS is essential for a more complete picture of the disease pathology and novel therapeutic targets. We here review the current knowledge about ILCs in the development and progression of MS and preclinical models of MS and discuss their potential for therapeutic applications. NH and DG are supported by a grant from the Austrian Science Fund (FWF): ZK-81B. SM is supported by the JESH program of the Austrian Academy of Sciences. BB is supported by the Fonds voor Wetenschappelijk Onderzoek (FWO), the Belgian Charcot Foundation, Stichting MS Research, Multiple Sclerosis International Federation (MSIF) and MoveS. Wewant to thank our laboratorymembers and the entire Peptaides/ ZK-81B community as well as K. Klein for numerous discussions and to apologize to all investigators whose research was not cited. BioRender.com was used for all Figures.

Additional file 1. Figure S1. Example of the gating strategy used to distinguish different immune cell subsets. Representative spleen sample from a PBS-treated hu/m TNFR2-ki mouse sacrificed at 25 days post immunization. Figure S2. Blocking TNFR1 with and without a TNFR2 agonist limits EAE development by decreasing demyelination while increasing lymphocyte numbers in the spinal cord. Figure S3. EHD2-scTNFR2 and ATROSIMAB treatments increase the level of anti-drug antibodies in serum but do not affect clinical EAE development. Figure S4. Frequency of immune cell subsets in inguinal lymph nodes and spleen. Figure S5. APP staining of spinal cord sections from representative mice from the acute cohort shows that axonal degeneration increases similarly to demyelination. Table S1. Primary antibodies used for immunohistochemistry and flow cytometry. Table S2. Clinical EAE development in hu/m TNFR1-ki x hu/m TNFR2 -ki mice treated either with PBS, a human TNFR2 agonist (EHD2-scTNFR2) and/or a human TNFR1 antagonist (ATROSIMAB).

Once regarded as an experimental artefact, cytotoxic CD4(+) T cells (CD4 CTL) are presently recognized as a biologically relevant T cell subset with important functions in anti-viral, anti-tumor, and autoimmune responses. Despite the potentially large impact on their micro-environment, the absolute cell counts of CD4 CTL within the peripheral circulation are relatively low. With the rise of single cell analysis techniques, detection of these cells is greatly facilitated. This led to a renewed appraisal of CD4 CTL and an increased insight into their heterogeneous nature and ontogeny. In this review, we summarize the developmental path from naive CD4(+) T cells to terminally differentiated CD4 CTL, and present markers that can be used to detect or isolate CD4 CTL and their precursors. Subsets of CD4 CTL and their divergent functionalities are discussed. Finally, the importance of local cues as triggers for CD4 CTL differentiation is debated, posing the question whether CD4 CTL develop in the periphery and migrate to site of inflammation when called for, or that circulating CD4 CTL reflect cells that returned to the circulation following differentiation at the local inflammatory site they previously migrated to. Even though much remains to be learned about this intriguing T cell subset, it is clear that CD4 CTL represent interesting therapeutic targets for several pathologies. CH received funds from Stichting MS Research. GD received funds from Charcot Stichting. NH received funds from FWO and Charcot Stichting. BB received funds from Charcot Stichting, MSIF, MoveS, and Stichting MS Research

Multiple sclerosis (MS) is an autoimmune disorder causing demyelination and neurodegeneration in the central nervous system. MS is characterized by disturbed motor performance and cognitive impairment. Current MS treatments delay disease progression and reduce relapse rates with general immunomodulation, yet curative therapies are still lacking. Regulatory T cells (Tregs) are able to suppress autoreactive immune cells, which drive MS pathology. However, Tregs are functionally impaired in people with MS. Interestingly, Tregs were recently reported to also have regenerative capacity. Therefore, experts agree that Treg cell therapy has the potential to ameliorate the disease. However, to perform their local anti-inflammatory and regenerative functions in the brain, they must first migrate across the blood-brain barrier (BBB). This review summarizes the reported results concerning the migration of Tregs across the BBB and the influence of Tregs on migration of other immune subsets. Finally, their therapeutic potential is discussed in the context of MS. Fonds voor Wetenschappelijk Onderzoek (FWO, 1S87418N) and Belgian Charcot Foundation.

Autoimmunity is caused by an unbalanced immune system, giving rise to a variety of organ-specific to system disorders. Patients with autoimmune diseases are commonly treated with broad-acting immunomodulatory drugs, with the risk of severe side effects. Regulatory T cells (Tregs) have the inherent capacity to induce peripheral tolerance as well as tissue regeneration and are therefore a prime candidate to use as cell therapy in patients with autoimmune disorders. (Pre)clinical studies using Treg therapy have already established safety and feasibility, and some show clinical benefits. However, Tregs are known to be functionally impaired in autoimmune diseases. Therefore, ex vivo manipulation to boost and stably maintain their suppressive function is necessary when considering autologous transplantation. Similar to autoimmunity, severe coronavirus disease 2019 (COVID-19) is characterized by an exaggerated immune reaction and altered Treg responses. In light of this, Treg-based therapies are currently under investigation to treat severe COVID-19. This review provides a detailed overview of the current progress and clinical challenges of Treg therapy for autoimmune and hyperinflammatory diseases, with a focus on recent successes of ex vivo Treg manipulation. The authors are funded by Fonds voor Wetenschappelijk Onderzoek (FWO), the Belgian Charcot Stichting, Stichting MS Research, MS International Foundation, and MoveS.

Additional file 3: Table S3. Primer sequences.

Additional file 4: Figure S1. Graphical summary of experimental designs. Graphical representation of the timing of carnosine treatment, EAE induction and sacrifice (tissue collection) for (a) analyses of control vs. EAE mice (data shown in Figure 2, Figure 3, Figure S2, Figure S3, Figure S4); (b) analysis of tissue carnosine loading in EAE (data shown in Figure 4); and (c) analyses of dose-dependent carnosine treatment effects (data shown in Figure 5, Figure 6, Figure S5, Figure S6). Figure S2. Spinal cord inflammatory activity during EAE. (a) Spinal cord mRNA expression in different stages of EAE compared to healthy controls (dashed line). n=6 animals/group. (b) Immunohistochemistry-based quantification of F4/80+ microglia/macrophage numbers in the spinal cord in different stages of EAE compared to healthy controls (dashed line). n=6 animals/group. Gene expression (a) and microglia/macrophage numbers (b) were increased in EAE vs. healthy controls (statistics not shown). Data are mean �� SD. One-way ANOVA or Kruskal-Wallis, post hoc testing *p

Additional file 2: Table S2. Oral carnosine treatment attenuates clinical disability in a monophasic rat EAE model.

Additional file 1: Table S1. Clinical details of human brain tissue.