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Inhibition of follicular T-helper cells by CD8+ regulatory T cells is essential for self tolerance


The ability to produce vigorous immune responses that spare self tissues and organs depends on the elimination of autoreactive T and B cells. However, purging of immature and mature self-reactive T and B cells is incomplete and may also require the involvement of cells programmed to suppress immune responses1. Regulatory T cells (Treg) belonging to the CD4+ T-cell subset may have a role in preventing untoward inflammatory responses, but T-cell subsets programmed to inhibit the development of autoantibody formation and systemic-lupus-erythematosus-like disease have not yet been defined2. Here we delineate a CD8+ regulatory T-cell lineage that is essential for the maintenance of self tolerance and prevention of murine autoimmune disease. Genetic disruption of the inhibitory interaction between these CD8+ T cells and their target Qa-1+ follicular T-helper cells results in the development of a lethal systemic-lupus-erythematosus-like autoimmune disease. These findings define a sublineage of CD8 T cells programmed to suppress rather than activate immunity that represents an essential regulatory element of the immune response and a guarantor of self tolerance.

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Figure 1: B6 Qa-1(D227K) mice develop an autoimmune phenotype.
Figure 2: Germinal-centre formation and antibody response in B6 Qa-1 (wild-type) and B6 Qa-1(D227K) mice challenged with protein antigen or virus.
Figure 3: CD44 + ICOSL + CD8 + cell population targets T FH to block generation of high-affinity antibodies.
Figure 4: Mechanism of Qa-1-restricted suppression by CD8 T reg cells.


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We thank R. Bronson (DF/HCC Rodent Histopathology Core) for histology analysis, R. Gelman and J. Yang for help with statistical analyses, C. Daniel and T. Kreslavsky for cytometry support and critical discussions, M. Iannacone and U. von Andrian for LCMV, X. Wang for technical assistance, M. Call, D. A. Alvarez Arias, T. Kadakia and A. Angel for manuscript and figure preparation. This work was supported in part by NIH Research Grant AI 037562, the Lupus Research Institute and a gift from the Schecter Research Foundation to H.C.; National Research Service Award Fellowships (DFCI/NCI T32 CA070083) to H.-J.K. and (HSPH/NCI T32 CA009382) to X.T.; and a Belgian American Educational Foundation Fellowship to B.V.

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H.-J.K. and H.C. conceived and planned experiments; H.-J.K., B.V., X.T. and L.L. performed experiments; H.-J.K. and H.C. analysed data and wrote the paper.

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Correspondence to Harvey Cantor.

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The authors declare no competing financial interests.

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Kim, HJ., Verbinnen, B., Tang, X. et al. Inhibition of follicular T-helper cells by CD8+ regulatory T cells is essential for self tolerance. Nature 467, 328–332 (2010).

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