Cellular Origins and Pathogenesis of Gastrointestinal NK- and T-Cell Lymphoproliferative Disorders

SIMPLE SUMMARY: Intestinal T- and NK-cell lymphoproliferative disorders are a group of rare gastrointestinal disorders that arise from immune cells in the intestinal mucosa that are also relatively unknown. Diseases such as indolent T-cell lymphoproliferative disorders of the gastrointestinal tract do not even require treatment, whereas others, such as monomorphic epitheliotropic intestinal T-cell lymphoma, will generally cause death within a year. No effective treatment is currently available, as little is known about how these tumours form or even what cells they arise from. This article summarizes the current state of knowledge about the main types of immune cells in the gastrointestinal mucosa and the processes by which they may transform into neoplasms. The clinical behaviour, pathological appearances and the molecular alterations that underlie these diseases are also discussed. ABSTRACT: The intestinal immune system, which must ensure appropriate immune responses to both pathogens and commensal microflora, comprises innate lymphoid cells and various T-cell subsets, including intra-epithelial lymphocytes (IELs). An example of innate lymphoid cells is natural killer cells, which may be classified into tissue-resident, CD56(bright) NK-cells that serve a regulatory function and more mature, circulating CD56(dim) NK-cells with effector cytolytic properties. CD56(bright) NK-cells in the gastrointestinal tract give rise to indolent NK-cell enteropathy and lymphomatoid gastropathy, as well as the aggressive extranodal NK/T cell lymphoma, the latter following activation by EBV infection and neoplastic transformation. Conventional CD4+ TCRαβ+ and CD8αβ+ TCRαβ+ T-cells are located in the lamina propria and the intraepithelial compartment of intestinal mucosa as type ‘a’ IELs. They are the putative cells of origin for CD4+ and CD8+ indolent T-cell lymphoproliferative disorders of the gastrointestinal tract and intestinal T-cell lymphoma, NOS. In addition to such conventional T-cells, there are non-conventional T-cells in the intra-epithelial compartment that express CD8αα and innate lymphoid cells that lack TCRs. The central feature of type ‘b’ IELs is the expression of CD8αα homodimers, seen in monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), which primarily arises from both CD8αα+ TCRαβ+ and CD8αα+ TCRγδ+ IELs. EATL is the other epitheliotropic T-cell lymphoma in the GI tract, a subset of which arises from the expansion and reprograming of intracytoplasmic CD3+ innate lymphoid cells, driven by IL15 and mutations of the JAK-STAT pathway.