Immunoglobulin-like transcript receptors on human dermal CD14⁺dendritic cells act as a CD8-antagonist to control cytotoxic T cell priming

Abstract

Human Langerhans cells (LCs) are highly efficient at priming cytolytic CD8 + T cells compared with dermal CD14 + dendritic cells (DCs). Here we show that dermal CD14 + DCs instead prime a fraction of naïve CD8 + T cells into cells sharing the properties of type 2 cytokinesecreting CD8 + T cells (TC2). Differential expression of the CD8-antagonist receptors on dermal CD14 + DCs, the Ig-like transcript (ILT) inhibitory receptors, explains the difference between the two types of DCs. Inhibition of CD8 function on LCs inhibited cytotoxic T lymphocytes (CTLs) and enhanced TC2 generation. In addition, blocking ILT2 or ILT4 on dermal CD14 + DCs enhanced the generation of CTLs and inhibited TC2 cytokine production. Lastly, addition of soluble ILT2 and ILT4 receptors inhibited CTL priming by LCs. Thus, ILT receptor expression explains the polarization of CD8 + T-cell responses by LCs vs. dermal CD14 + DCs.D endritic cells (DCs) are potent antigen-presenting cells (APCs) responsible for inducing Ag-specific immunity and tolerance (1). Several populations of DCs take up residence in different tissues and carry common as well as unique biological functions (2, 3). The healthy human skin displays at least three DC populationsLangerhans cells (LCs) in the epidermis and interstitial CD1a + and CD14 + DCs in the dermis (4, 5). Each of the different skin DC subsets carries out specialized functions. CD14 + DCs that reside in the dermis are particularly efficient at controlling the differentiation of naïve B cells into plasma cells (6, 7). Epidermal LCs, conversely, are highly efficient at priming naïve CD8 + T cells into potent cytotoxic T lymphocytes (CTLs). Both DC subsets are equally efficient at inducing a secondary CD8 + T-cell response (7-9).T lymphocytes are also composed of subsets. The CD4 + T-cell subsets, Th1 and Th2 (10), were the first to be characterized. Subsequently, other subsets have been identified and include Tregs, Th17, Tfh, and Th9 (11). CD8 + T-cell subsets have also been divided into subsets based on their cytokine production profile (12)(13)(14). Type 1 cytokine-producing T cells (TC1) express IFN-γ and TNF-α, whereas type 2 cytokine-producing T cells (TC2) produce IL-4, -5, and -13. Suppressor CD8 + T cells produce IL-10 and TGF-β and are characterized by low expression levels of CD8 and CD28 (15,16). These findings are physiologically relevant because the balance between TC1 to TC2 and CD8 + suppressor T cell populations correlates with a patient's ability to overcome tumor overgrowth or viral infections.Studies with CD8-α or CD8-β gene-targeted mice have revealed that CD8 plays a key role in the maturation and function of MHC class I-restricted T lymphocytes (17,18). Interacting with MHC in the immunological synapse, a specialized junction between a T lymphocyte and an APC, CD8 can enhance the affinity of T-cell receptor (TCR)-CD8 complexes for MHC-peptide (pMHC) complexes by ∼10-fold (19). The importance of CD8 is also demonstrated by the function of two inhibitory receptors, ILT2 and ILT4, that can...

In situloading of skin dendritic cells with apoptotic bleb-derived antigens for the induction of tumor-directed immunity

“…It has recently been described that CD14 C DDCs are far less potent in effectively priming CD8 C T cells to differentiate into cytotoxic effector cells, as compared to CD1a C DDCs and LCs, and moreover induce regulatory T cells, a process driven by the production of IL-10 and the expression of Ig-like transcript inhibitory receptors. [32][33][34] Interestingly, next to the predominant migration of CD1a C DDCs and a significant increase in uptake by this potent DDC subset, injecting 4/GM greatly diminished the migration of CD14…”

“…The modest increased uptake of blebs compared to ACR (14.8% versus 9.2%, respectively), and thereby the higher number of MART-1 [26][27][28][29][30][31][32][33][34][35] presenting skin DCs, is unlikely to be solely responsible for the selective activation of the TAA-specific CD8 C CTLs. It is known that heat shock proteins (HSPs), previously described to be present at high levels in apoptotic blebs, 35 greatly facilitate cross-presentation.…”

“…12 This effect is most likely mediated by IL-10, as co-culture of IL-10-conditioned skin emigrated DC with T cells leads to a diminished T-cell proliferation, T H 2 skewing, an increase in regulatory T cells, and a reduced priming of functional cytotoxic T cells. 12,[32][33][34] The negative modulation of the skin surrounding the tumor area, or even systemically under advanced metastatic conditions, can thereby hamper i.d. vaccination strategies.…”

“…C and CD8 C T-cell proliferation (n D 7). (B) DCs that egressed from the skin biopsies after injecting either wild-type or MART-1 expressing apoptotic cell remnants (ACRs) or blebs, were co-cultured with a MART-1 [26][27][28][29][30][31][32][33][34][35] recognizing and HLA-A2 restricted cytotoxic T lymphocyte (CTL) line (> 95% pure) for 24 hours. Antigen-specific activation was determined by deducting the levels of interferon g (IFNg) produced following the injection of wild-type ACRs or blebs from the levels produced after injecting MART-1 expressing apoptotic fractions (n D 3).…”

“…injected in skin explants from HLA-A2 positive donors in the presence of 4/GM, and skin DC were harvested after 48-72 hours. After a subsequent 24 hours of co-culture with a MART-1 [26][27][28][29][30][31][32][33][34][35] recognizing CTL line (HLA-A2 restricted; >95% pure), the supernatant was analyzed for the presence of IFNg, as a measure of cross-presentation of the MART-1 [26][27][28][29][30][31][32][33][34][35] epitope by egressed DC. The MART-1 [26][27][28][29][30][31][32][33][34][35] specific IFNg production was assessed by deducting the IFNg production following a co-culture with DC from wild-type ACR or blebs injected skin, from that secreted after co-culturing with DC from MART-1-transduced ACR or blebs (D IFNg, Fig.…”