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...
Critical to the development of novel vaccines is the availability of in vivo models of the human immune system that permit testing of vaccine efficacy. Here, we used NOD/SCID beta2m −/− immunodeficient mice which, when engrafted with human CD34+ hematopoietic progenitors, develop all subset of human dendritic cells (DCs) and B cells. T cells and their subsets can be reconstituted by adoptive transfer. We show that these mice can generate recall CD8+ T cell responses upon exposure to seasonal influenza virus vaccines i) live attenuated trivalent vaccine, i.e. FluMist; or ii) killed trivalent vaccine, i.e., Fluzone. CD8+ T cells specific to at least two influenza antigens FluM1 and NS1 can be detected in the blood of mice vaccinated with FluMist but not in mice vaccinated with Fluzone. Specific T cells are also present in the spleen and peripheral tissues (lung) demonstrating that human T cells can utilize murine signals for trafficking and extravasation. Upon short‐term ex vivo antigen exposure CD8+ T cells produce IFN‐g and express surface CD107 consistent with their acquisition of effector function. Response to vaccination is dependent upon reconstitution of the human hematopoietic system. Thus, vaccine antigens can be cross‐presented by endogenous human antigen presenting cells in humanized mice. Therefore, this model might be useful for testing vaccines oriented towards generation of cellular immunity.
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