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The skin represents a specialized site for immune surveillance consisting of resident, inflammatory and memory populations of lymphocytes. The entry and retention of T cells, B cells, and ILCs is tightly regulated to facilitate detection of pathogens, inflammation and tumors cells. Loss of individual or multiple populations in the skin may break tolerance or increase susceptibility to tumor growth and spread. Studies have significantly advanced our understanding of the role of skin T cells and ILCs at steady state and in inflammatory settings such as viral challenge, atopy, and autoimmune inflammation. The knowledge raised by these studies can benefit to our understanding of immune cell trafficking in primary melanoma, shedding light on the mechanisms of tumor immune surveillance and to improve immunotherapy. This review will focus on the T cells, B cells, and ILCs of the skin at steady state, in inflammatory context and in melanoma. In particular, we will detail the core chemokine and adhesion molecules that regulate cell trafficking to and within the skin, which may provide therapeutic avenues to promote tumor homing for a team of lymphocytes.

T-dependent humoral immune responses to infection involve a collaboration between B and CD4 T cell activation, migration, and co-stimulation, thereby culminating in the formation of germinal centers (GCs) and eventual differentiation into memory cells and long-lived plasma cells (PCs). CD4 T cell-derived signals drive the formation of a tailored B cell response. Downstream of these signals are transcriptional regulators that are the critical enactors of immune cell programs. In particular, a core group of transcription factors regulate both B and T cell differentiation, identity, and function. The timing and expression levels of these transcription factors are tightly controlled, with dysregulated expression correlated to immune cell dysfunction in autoimmunity and lymphomagenesis. Recent studies have significantly advanced our understanding of both extrinsic and intrinsic regulators of autoreactive B cells and antibody-secreting PCs in systemic lupus erythematosus, rheumatoid arthritis, and other autoimmune conditions. Yet, there are still gaps in our understanding of the causative role these regulators play, as well as the link between lymphoid responses and peripheral damage. This review will focus on the genesis of immunopathogenic CD4 helper and GC B cells. In particular, we will detail the transcriptional regulation of cytokine and chemokine receptor signaling during the pathogenesis of GC-derived autoimmune conditions in both murine models and human patients.