Neutrophil Expression of Fas Ligand and Perforin Directs Effector CD8 T Cell Infiltration into Antigen-Challenged Skin

Abstract

Contact hypersensitivity (CHS) is a T cell response to hapten skin challenge of sensitized individuals proposed to be mediated by hapten-primed CD8 cytolytic T cells. Effector CD8 T cell recruitment into hapten challenge sites to elicit CHS requires prior CXCL1- and CXCL2-mediated neutrophil infiltration into the site. We investigated whether neutrophil activities directing hapten-primed CD8 T cell skin infiltration in response to 2, 4-dinitrofluorobenzene (DNFB) required FasL and perforin expression. Although DNFB sensitization of gld/perforin−/− mice induced hapten-specific CD8 T cells producing IFN-γ and IL-17, these T cells did not infiltrate the DNFB challenge site to elicit CHS but did infiltrate the challenge site and elicit CHS when transferred to hapten challenged naïve wild-type recipients. Hapten-primed wild-type CD8 T cells, however, did not elicit CHS when transferred to naïve gld/perforin−/− recipients. Wild-type bone marrow neutrophils expressed FasL and perforin and when transferred to sensitized gld/perforin−/− mice, restored hapten-primed CD8 T cell infiltration into the challenge site and CHS. The FasL/perforin-mediated activity of wild-type neutrophils induced the expression of T cell chemoattractants, CCL1, CCL2, and CCL5, within the hapten challenged skin. These results indicate FasL/perforin independent functions of hapten-primed CD8 T cells in CHS and identify new functions for neutrophils in regulating effector CD8 T cell recruitment and immune responses in the skin.

Leukotriene B4—leukotriene B4 receptor axis promotes oxazolone‐induced contact dermatitis by directing skin homing of neutrophils and CD8+ T cells

“…3,7 We confirmed these findings by showing that neutrophil depletion greatly blocked the skin infiltration of CD8 + T cells following OXA challenge. Several T-cell chemokines including CXCL9 and CXCL10 have been shown to be important for the skin homing of T cells; 5,6,27 however, there was no change in gene expression of CXCL9 and CXCL10 in OXA-challenged ears following blockade of the LTB 4 -BLT1 axis or neutrophil depletion, suggesting that other important mediators could be more important for the skin homing of CD8 + T cells in OXA-induced contact dermatitis.…”

“…3 Recent study further suggested that neutrophil expression of Fas ligand and perforin could promote CD8 + T-cell infiltration by inducing T-cell chemokine production in hapten-challenged skin. 7 These results together suggest a complex and dynamic cytokine network in the regulation of the skin recruitment of hapten-primed CD8 + T cells and neutrophils following hapten challenge during the elicitation phase.…”

“…4 Hapten-primed CD8 + T cells have been shown to quickly migrate to the vasculature of hapten-challenged skin and direct early recruitment of neutrophils, which in turn mediates subsequent skin recruitment of CD8 + T cells through various mechanisms. 3,7 Our data suggest a novel mechanism by which neutrophils amplify the skin recruitment of CD8 + T cells by producing LTB 4 . In summary, our study reveals the important pro-inflammatory role of the LTB 4 -BLT1 axis in the development of contact dermatitis by attracting neutrophil and CD8 + effector T cells to hapten-challenged skin.…”

Mechanisms of graft rejection after lung transplantation

“…Thus, the role of PMNs in promoting allograft injury has been extensively investigated in the past few years 31 . Besides their well-known effector functions, PMNs can also recruit activated CD8 + T cells through Fas ligand expression 32 . PMNs also facilitate antigen presenting cell (APC) activity, which is critical to T cell activation and differentiation, through the expression of MHC class II and co-stimulatory molecules 33 .…”

The lymphocyte transformation test in allergic contact dermatitis: New opportunities

“…ACD is, at least in part, a cytotoxic T-cell-mediated immune response (Kehren et al, 1999;Kish et al, 2012). Granzyme B-and IFNg production (measured by ELISA or ELISpot) have been used as endpoints for cytotoxicity drug-allergic responses (Porebski et al, 2013) and could also be used for ACD.…”