Unique phenotype of human tonsillar and in vitro-induced FOXP3+CD8+ T cells.
Forkhead box p3 (FOXP3) is known to program the acquisition of suppressive capacities in CD4(+) regulatory T cells (Treg), whereas its role in CD8(+) T cells is unknown. The current study investigates whether FOXP3 also acts as a Treg master switch in peripheral blood and tonsillar CD8(+) T cells. Single-cell analyses reveal the existence of a FOXP3(+)CD8(+) population in human tonsils, whereas FOXP3(+)CD8(+) T cells are rarely detected in peripheral blood. Tonsillar FOXP3(+)CD8(+) T cells exhibit a Treg phenotype with high CTLA-4 and CD45RO and low CD127 and CD69 expression. Interestingly, the tonsillar FOXP3(+)CD8(+) T cells are mostly CD25(negative) and some cells also express the proinflammatory cytokines TNF-alpha, IFN-gamma, or IL-17A. Particularly, IL-17A-expressing cells are present among FOXP3(+)CD8(+) T cells. Even though FOXP3 expression is at the detection limit in peripheral blood CD8(+) T cells ex vivo, it can be induced in vitro in naive CD8(+) T cells by polyclonal stimulation. The induced FOXP3(+)CD8(+) T cells are predominantly CD25(high) and CD28(high) and similar to tonsillar cells, they produce high levels of TNF-alpha, IFN-gamma, and granzyme B. However, IL-4 expression is mutually exclusive and IL-17A expression is not detectable. These FOXP3(+)CD8(+) T cells suppress the proliferation of CD4(+) T cells in cocultures, while showing no direct cytotoxic activity. In conclusion, the current study characterizes FOXP3-expressing CD8(+) T cells from human tonsils and shows that in vitro activation leads to FOXP3 expression in CD8(+) T cells and gain of suppressive activity.
Siegmund
Kerstin
K
Swiss Institute of Allergy and Asthma Research, University of Zurich, Davos, Switzerland.
Rückert
Beate
B
Ouaked
Nadia
N
Bürgler
Simone
S
Speiser
Andreas
A
Akdis
Cezmi A
CA
Schmidt-Weber
Carsten B
CB
D015153:Blotting, Western; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018920:Coculture Techniques; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D051858:Forkhead Transcription Factors / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology*; D014066:Palatine Tonsil / Q000166:cytology* / Q000276:immunology; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism
D018106:CD28 Antigens; D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit