A novel humanized mouse model to study the function of human cutaneous memory T cells in vivo in human skin

Abstract

Human skin contains a population of memory T cells that support tissue homeostasis and provide protective immunity. T cell function in human skin is difficult to study due to a lack of adequate in vivo models. Thus, we utilized immunodeficient NOD-scid IL2rγ null (NSG) mice that carried in vivo-generated engineered skin (ES) and received adoptively transferred human peripheral blood mononuclear cells to follow the migration and function of circulating human memory T cells in human ES in vivo. ES were generated from human keratinocytes and fibroblasts only and initially contained no skin-resident immune cells. This reductionist system allowed us to study human T cell recruitment into non-inflamed and non-infected human skin, reflecting physiological skin conditions. Circulating human memory T cells preferentially infiltrated the human ES and these had the diverse functional profiles of T cells found in fresh human skin. Importantly, the chemokine and cytokine microenvironment found in the ES closely resembled that of non-inflamed human skin, which supports T cell maintenance and function. Upon entering the ES T cells assumed a resident memory T celllike phenotype in the absence of infection and these cutaneous T cells were activated locally upon injection of Candida albicans that was presented by autologous monocyte derived dendritic cells within the human ES. In summary, we have generated a novel mouse model with broad utility in studies of the dynamics of human cutaneous memory T cell generation, antigen-specific memory T cell responses, and the role of the skin microenvironment to skin immunity in vivo.

Challenging Cutaneous T-Cell Lymphoma: What Animal Models Tell us So Far

“…Owing to the low take rate, primary cell engraftment requires murine strains devoid of functional T cells, B cells, and NK cells, precluding the study of the contribution of the immune response to therapies, a problem that could be overcome using humanized PDX models (Ito et al, 2009;Klicznik et al, 2020). On the other hand, M2-like macrophages are still present in NSG mice, and their role has been described as important not only in the engraftment of MF/SS but also in disease progression (Assaf and Hwang, 2016;Wu et al, 2014).…”

Evolving Experimental Platforms to Evaluate Ulcerative Colitis

“…These include skin transplantation models, PD-1 therapy, the development of transplanted humanized lymphoid and myeloid cells, chronic lymphocytic leukemia studies, and many others. [107][108][109][110] NSG mice possess mutations on the NOD/ShiLtJ genetic background and exhibit severe SCID (mutation in the Prkdc protein that impairs the mice from producing T and B cells) along with a complete null allele of the IL-2 receptor common gamma chain. The null allele for the IL-2Rγ abrogates cytokine signaling via multiple receptors and this leads to dysfunctional natural killer (NK) cells.…”

The intestinal flora of patients with GHPA affects the growth and the expression of PD-L1 of tumor

“…CD45 + and CD3 + cells in the peripheral blood of mice were determined by flow cytometry to verify the results of immune remodeling. When CD45 + cells can be detected in the peripheral blood of mice, the immune reductionist is considered to be successful, and CD3 + cells confirmed the presence of T cells [20][21][22].…”