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.
