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Most memory phenotype (MP) CD44hi CD8+ cells are resting interleukin (IL)-15-dependent cells characterized by high expression of the IL-2/IL-15 receptor β (CD122). However, some MP CD8+ cells have a CD122lo phenotype and are IL-15 independent. Here, evidence is presented that the CD122lo subset of MP CD8+ cells is controlled largely by major histocompatibility complex (MHC) class I molecules. Many of these cells display surface markers typical of recently activated T cells (CD62Llo, CD69hi, CD43hi, and CD127lo) and show a high rate of background proliferation. Cells with this phenotype are highly enriched in common γ chain-deficient mice and absent from MHC-I-/- mice. Unlike CD122hi CD8+ cells, CD122lo MP CD8+ cells survive poorly after transfer to MHC-I-/- hosts and cease to proliferate. Although distinctly different from typical antigen-specific memory cells, CD122lo MP CD8+ cells closely resemble the antigen-dependent memory CD8+ cells found in chronic viral infections. [ABSTRACT FROM AUTHOR]

In conditions of T lymphopenia, interleukin (IL) 7 levels rise and, via T cell receptor for antigen-self-major histocompatibility complex (MHC) interaction, induce residual naive T cells to proliferate. This pattern of lymphopenia-induced "homeostatic" proliferation is typically quite slow and causes a gradual increase in total T cell numbers and differentiation into cells with features of memory cells. In contrast, we describe a novel form of homeostatic proliferation that occurs when naive T cells encounter raised levels of IL-2 and IL-15 in vivo. In this situation, CD8(+) T cells undergo massive expansion and rapid differentiation into effector cells, thus closely resembling the T cell response to foreign antigens. However, the responses induced by IL-2/IL-15 are not seen in MHC-deficient hosts, implying that the responses are driven by self-ligands. Hence, homeostatic proliferation of naive T cells can be either slow or fast, with the quality of the response to self being dictated by the particular cytokine (IL-7 vs. IL-2/IL-15) concerned. The relevance of the data to the gradual transition of naive T cells into memory-phenotype (MP) cells with age is discussed.

Psoriasis is one of the most common T cell-mediated autoimmune diseases in humans. Although a role for the innate immune system in driving the autoimmune T cell cascade has been proposed, its nature remains elusive. We show that plasmacytoid predendritic cells (PDCs), the natural interferon (IFN)-alpha-producing cells, infiltrate the skin of psoriatic patients and become activated to produce IFN-alpha early during disease formation. In a xenograft model of human psoriasis, we demonstrate that blocking IFN-alpha signaling or inhibiting the ability of PDCs to produce IFN-alpha prevented the T cell-dependent development of psoriasis. Furthermore, IFN-alpha reconstitution experiments demonstrated that PDC-derived IFN-alpha is essential to drive the development of psoriasis in vivo. These findings uncover a novel innate immune pathway for triggering a common human autoimmune disease and suggest that PDCs and PDC-derived IFN-alpha represent potential early targets for the treatment of psoriasis.

Psoriasis is a common T cell-mediated autoimmune disorder where primary onset of skin lesions is followed by chronic relapses. Progress in defining the mechanism for initiation of pathological events has been hampered by the lack of a relevant experimental model in which psoriasis develops spontaneously. We present a new animal model in which skin lesions spontaneously developed when symptomless prepsoriatic human skin was engrafted onto AGR129 mice, deficient in type I and type II interferon receptors and for the recombination activating gene 2. Upon engraftment, resident human T cells in prepsoriatic skin underwent local proliferation. T cell proliferation was crucial for development of a psoriatic phenotype because blocking of T cells led to inhibition of psoriasis development. Tumor necrosis factor-alpha was a key regulator of local T cell proliferation and subsequent disease development. Our observations highlight the importance of resident T cells in the context of lesional tumor necrosis factor-alpha production during development of a psoriatic lesion. These findings underline the importance of resident immune cells in psoriasis and will have implications for new therapeutic strategies for psoriasis and other T cell-mediated diseases.