Stromal cells control the epithelial residence of DCs and memory T cells by regulated activation of TGF-β

Abstract

Cells of the immune system that reside in barrier epithelia provide a first line of defense against pathogens. Langerhans cells (LCs) and CD8+ tissue-resident memory T cells (TRM cells) require active transforming growth factor-β1 (TGF-β) for epidermal residence. Here we found that integrins αvβ6 and αvβ8 were expressed in non-overlapping patterns by keratinocytes (KCs) and maintained the epidermal residence of LCs and TRM cells by activating latent TGF-β. Similarly, the residence of dendritic cells and TRM cells in the small intestine epithelium also required αvβ6. Treatment of the skin with ultraviolet irradiation decreased integrin expression on KCs and reduced the availability of active TGF-β, which resulted in LC migration. Our data demonstrated that regulated activation of TGF-β by stromal cells was able to directly control epithelial residence of cells of the immune system through a novel mechanism of intercellular communication.

The Interaction Between Human Papillomaviruses and the Stromal Microenvironment

“…As discussed above, local TGFβ is critical for the differentiation and maintenance of LCs 77,289,306,312–316 . TGFβ also prevents DC migration, downregulates MHC-II, and promotes tolorogenic DC maturation which can promote tumor-specific Treg development 94 .…”

“…Resident memory T cells (T RM s) are memory cells positioned in the tissue, poised to reactivate in response to antigen 289–291 . Little is known about how these cells function in the context of HPV infection.…”

“…Loss of TGFβ1 expression by both LCs and keratinocytes completely prevents LC differentiation and results in the absence of LCs 77,289,306,312–316 . Maintenance of LCs in epidermis also requires TGFβ: loss of TGFβ signaling in LCs results in mass migration to regional lymph nodes 289,314,315 . Interestingly, autocrine TGFβ1 expression in LCs seems to be important in LC maintenance in the skin, but activation of TGFβ1 is achieved by KC-derived integrins 289 .…”

“…Maintenance of LCs in epidermis also requires TGFβ: loss of TGFβ signaling in LCs results in mass migration to regional lymph nodes 289,314,315 . Interestingly, autocrine TGFβ1 expression in LCs seems to be important in LC maintenance in the skin, but activation of TGFβ1 is achieved by KC-derived integrins 289 . Thus both cell types cooperate to maintain the pool of LCs needed for immune surveillance.…”

“…Thus both cell types cooperate to maintain the pool of LCs needed for immune surveillance. T RM s also require the integrins and TGFβ to develop and remain in the skin 289–291 . GM-CSF and IL34, which bind to the same receptor, seem to play a critical role in LC differentiation and maintenance combination with TGFβ 302,313,317,318 .…”