More so than other organs, skin resident T cell repertoires differ fundamentally between mice and humans. For example, mouse skin contains large numbers ofγδ T cells with Vγ5+
invariant TCRs known as dendritic epidermal T cells (DETC), whose development requires skint1, a immunoglobulin-like dermal protein 52
. Human skin lacks skint1 and DETC, and instead contains predominantly T cells that express rearranged αβ TCRs 53, 54
. During the evolution of muroid rodents, a break in chromosome 1 resulted in a loss of group 1 CD1 genes, so human, but not mouse skin, contains Langerhans cells that express very high density CD1a 13
. These general observations highlight two key reasons for developing experimental systems for studying skin T cell immunity in humans. First, the natural functions of CD1a cannot be studied in mice. Second, CD1a and other immune receptors, which naturally differ between these two species, represent candidate molecules for controlling the dichotomously different organization of skin T cell populations seen in these species.
In mice, IL-22 is typically co-secreted with IL-17 and is usually understood as part of the TH
17 phenotype 55
, although overexpression of Notch results in production of IL-22 in the absence of IL-17 56
. Human αβ T cells producing IL-22 in the absence of IL-17 have been frequently observed and are now emerging as a recognized T helper subset, TH
22 cells express the aryl hydrocarbon receptor 50
, skin-homing chemokine receptors (CCR4, CCR10) 47,48
, and localize to healthy and diseased skin 49
. Although the antigen presenting molecules or any molecular targets recognized by TH
22 cells are currently unknown, CD1a represents a good candidate because it is absent in mice and highly expressed in tissues that are enriched in TH
22 cells. Here we show that CD1a autoreactive T cells have all of the known properties of TH
22 cells, thereby identifying CD1a as molecular target of TH
22 cells. Determining the relative contribution of CD1a and MHC antigen presenting molecules in TH
22 cell activation will be important for understanding and intervening in skin immunopathology caused by IL-22 in psoriasis and other skin diseases 46, 49
. More generally, our data show that populations of CD1a-autoreactive T cells are abundantly present in the blood and skin of most human donors tested and so we conclude that they are a normal part of the humanαβ T cell repertoire.
The experimental system we have generated is unbiased in the sense that it is able to detect responses against any CD1 protein, but T cell activation by CD1a dominated in magnitude of response and the percentage of individuals responding in both blood and skin-derived T cells. An obvious possibility to explain these findings is that CD1a-autoreactive T cells may be as or more common than T cells recognizing other CD1 isoforms in unchallenged human hosts. The estimated precursor frequency for CD1a-autoreactive T cells among memory T cells in the blood measured here with CD1a expressing cells (0.02 to 0.4 %) is similar to that found for human NKT cells measured with CD1d-α-galactosylceramide tetramers (undetectable to 1.0 %) 4, 5, 7
. Tetramer based detection of NKT cells is direct, but necessarily requires a priori
knowledge of antigens, measures responses to only one antigen and typically uses a synthetic superagonist, α-galactosyl ceramide. The detection system reported here differs in that it is presumably measuring responses to diverse and natural cellular self antigens, a speculation supported by data showing that lipid extracts of K562 cells activate CD1a autoreactive T cells (not shown). Given the incomplete current understanding of the diversity of self antigens for CD1 proteins, the features of this detection system were not only desirable, but also necessary to make the first global measurements of CD1 autoreactivity ex vivo
However, because this detection method requires an activation response, the number of cells detected depends on activation thresholds. Therefore, the second possibility for the increased detection of CD1a-autoreactive cells is that they have a lower threshold of activation than T cells recognizing other CD1 proteins. Because CD1a is generally absent or low in peripheral blood and tissues other than skin, CD1a-autoreactive T cell contact with CD1a-expressing APCs is not expected to be a common event in the blood and most other tissues. This situation contrasts to CD1d, which is expressed on the peripheral blood B cells, monocytes and other cells in blood and tissues 16
. These considerations suggest a model in which CD1a-reactive T cell activation might have lower intrinsic resistance to activation and that their function is controlled by their ability to gain direct access to CD1a-expressing APCs in certain tissue environments.
Three related observations suggest that CD1a recognition occurs as a mechanism of skin homeostasis: restriction of CD1a expression to the skin, homing receptors (CLA, CCR6, CCR4, CCR10) that drive T cells to the skin and linkage of CD1a autoreactivity to the TH
22 phenotype. Rather than stimulating other hematopoietically derived immune cells, IL-22 acts on heterodimers of IL-10R2 and IL-22R1 expressed on epithelial cells, including keratinocytes 42
. Therefore, IL-22 secretion from chronic interactions with CD1a autoreactive TCRs on LCs might promote epithelial matrix remodeling in a baseline state without necessarily provoking broader immune activation or immunopathology 44
. However, IL-22 over-production promotes acanthosis observed in psoriasis 57
, and triggered release of the less abundant cytokines detected in CD1a autoreactive cells (IL-2, IL-13, IFN-γ) can promote immunopathology. These considerations drive ongoing efforts to understand regulation of the CD1a autoreactivity. Our preliminary data suggest that CD1a autoreactive T cells are present in dermis ( and data not shown), yet LCs mainly localize to the epidermis. Therefore, one model is that these near neighbors cross the dermal-epidermal junction to contact each other. Of course, skin is a rich source of tissue-specific oils and waxes that might function as CD1a presented lipid autoantigens.