Normality sensing licenses local T cells for innate-like tissue surveillance

Abstract

The increasing implication of lymphocytes in general physiology and immune surveillance outside of infection poses the question of how their antigen receptors might be involved. Here, we show that macromolecular aggregates of intraepidermal γδ T cell antigen receptors (TCRs) in the mouse skin aligned with and depended on Skint1, a butyrophilin-like (BTNL) protein expressed by differentiated keratinocytes (KCs) at steady state. Interruption of TCR-mediated ‘normality sensing’ had no impact on γδ T cell numbers but altered their signature phenotype, while the epidermal barrier function was compromised. In addition to the regulation of steady-state physiology, normality sensing licensed intraepidermal T cells to respond rapidly to subsequent tissue perturbation by using innate tumor necrosis factor (TNF) superfamily receptors. Thus, interfering with Skint1-dependent interactions between local γδ T cells and KCs at steady state increased the susceptibility to ultraviolet B radiation (UVR)-induced DNA damage and inflammation, two cancer-disposing factors.

Atypical sideways recognition of CD1a by autoreactive γδ T cell receptors

“…In mice, hypo-responsive γδ TCR signalling pathways have been broadly observed in vivo 41 , where hypo-responsiveness protects against negative selection. However, for mouse γδ T cells proximal signalling via TCRζ is preserved in ways that allow maintenance of cells and expansion in immunosurveillance niches 42 . The alternative possibility is that the high incidence binding angles and ‘head to side’ interactions, might not lead to productive TCR clustering and signalling.…”

“…Recent studies show that for mice, such hypo-responsiveness appears to be intrinsic to the γδCD3 complex and is a very broad phenomenon when measured in vivo 41 , 50 . Thus, mouse TCR hypo-responsiveness is increasingly viewed not as a defect of γδ T cell function, but instead as an adaptive response that confers protection against negative selection 41 , which allows colonisation and survival in the skin and other immunoregulatory niches in response to ‘normality sensing’ of local self-ligands 42 . Experimentally, human γδ T cells are difficult to expand ex vivo 32 , and our TCR clustering and signalling data hint at a possible comparative hypo-responsiveness in the human system.…”

Generation and proof-of-concept for allogeneic CD123 CAR-Delta One T (DOT) cells in Acute Myeloid Leukemia

“…CD123CAR-DOTs showed enhanced cytotoxicity over mock-DOTs against CD123  AML primary blasts in 48h assays (Fig2C). Moreover, compared to mock-DOTs, CD123CAR-DOTs produced significantly higher levels of master anti-tumor mediators, namely the cytokines TNF- and IFN-, as well as IL-13, recently implicated in orchestrating tumor surveillance in mice 31 ; the T-cell costimulator 4-1BB, a major determinant of  T cellmediated tissue surveillance 32 ; the signal transducer Axl, shown to maximize IL-15R signaling in human NK cell differentiation 33 ; the myeloid differentiation factor, GM-CSF; and the chemokines MIP-1a (CCL3), CCL5, CXCL13 and lymphotactin (XCL1), all important in mobilizing multiple leukocyte subsets in cancer immunity 34 .…”

The Trinity of Skin: Skin Homeostasis as a Neuro–Endocrine–Immune Organ

“…Underneath the barrier lies various immune cells, such as Langerhans cells (LCs), dendritic cells (DCs), mast cells (MCs), B and T lymphocytes, together with skin cells that constitute skin-associated lymphoid tissue (SALT) [ 72 ]. Under a steady state, these immune cells surveillance skin homeostasis and help maintain a balanced metabolism and barrier integrity [ 73 , 74 , 75 ]. When homeostasis is broken, SALT elicits it effect by recognizing the pathogen, modulating the cascade of the local immune responses and participating in the pathophysiology of autoimmune and hypersensitivity disorders [ 76 ].…”