CCR6 is expressed on an IL-10-producing, autoreactive memory T cell population with context-dependent regulatory function.
Interleukin (IL)-10 produced by regulatory T cell subsets is important for the prevention of autoimmunity and immunopathology, but little is known about the phenotype and function of IL-10-producing memory T cells. Human CD4(+)CCR6(+) memory T cells contained comparable numbers of IL-17- and IL-10-producing cells, and CCR6 was induced under both Th17-promoting conditions and upon tolerogenic T cell priming with transforming growth factor (TGF)-beta. In normal human spleens, the majority of CCR6(+) memory T cells were in the close vicinity of CCR6(+) myeloid dendritic cells (mDCs), and strikingly, some of them were secreting IL-10 in situ. Furthermore, CCR6(+) memory T cells produced suppressive IL-10 but not IL-2 upon stimulation with autologous immature mDCs ex vivo, and secreted IL-10 efficiently in response to suboptimal T cell receptor (TCR) stimulation with anti-CD3 antibodies. However, optimal TCR stimulation of CCR6(+) T cells induced expression of IL-2, interferon-gamma, CCL20, and CD40L, and autoreactive CCR6(+) T cell lines responded to various recall antigens. Notably, we isolated autoreactive CCR6(+) T cell clones with context-dependent behavior that produced IL-10 with autologous mDCs alone, but that secreted IL-2 and proliferated upon stimulation with tetanus toxoid. We propose the novel concept that a population of memory T cells, which is fully equipped to participate in secondary immune responses upon recognition of a relevant recall antigen, contributes to the maintenance of tolerance under steady-state conditions.
Rivino
Laura
L
Institute for Research in Biomedicine, Bellinzona, Switzerland.
Gruarin
Paola
P
Häringer
Barbara
B
Steinfelder
Svenja
S
Lozza
Laura
L
Steckel
Bodo
B
Weick
Anja
A
Sugliano
Elisa
E
Jarrossay
David
D
Kühl
Anja A
AA
Loddenkemper
Christoph
C
Abrignani
Sergio
S
Sallusto
Federica
F
Lanzavecchia
Antonio
A
Geginat
Jens
J
D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D005786:Gene Expression Regulation; D006706:Homeostasis / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D007165:Immunosuppression Therapy; D007371:Interferon-gamma / Q000235:genetics; D016753:Interleukin-10 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D054399:Receptors, CCR6 / Q000235:genetics*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
C106311:CCR6 protein, human; D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell; D054399:Receptors, CCR6; D016212:Transforming Growth Factor beta; D016753:Interleukin-10; D007371:Interferon-gamma