Dok-1 and Dok-2 Regulate the Formation of Memory CD8+ T Cells.
Diverse signals received by CD8+T cells are integrated to achieve the required magnitude of cell expansion and the appropriate balance of effector/memory CD8+T cell generation. Notably, the strength and nature of TCR signaling influence the differentiation and functional capacity of effector and memory CD8+T cells. Dok-1 and Dok-2, the two members of the Dok family expressed in T cells, negatively regulate TCR signaling in vitro. However, the role of Dok proteins in modulating T cell function in vivo has not yet studied. We studied the function of Dok-1 and Dok-2 proteins in the regulation of the CD8+T cell response to vaccinia virus infection. Comparison of responses to vaccinia virus expressing OVA peptide SIINFEKL by wild-type and Dok-1/2-/-CD8+OT-I cells showed that the absence of Dok-1 and Dok-2 slightly reduced the magnitude of virus-specific effector CD8+T cell expansion. This was not due to reduced proliferation or enhanced apoptosis of effector CD8+T cells. Dok-1/2-deficient effector CD8+T cells showed increased cell surface TCR expression following virus infection in vivo and increased expression of granzyme B and TNF upon stimulation with peptide Ag ex vivo. Finally, Dok-1/2-deficient effector CD8+T had a severe defect in survival that resulted in impaired generation of memory CD8+T cells. These results reveal the critical involvement of Dok-1 and Dok-2 in a negative-feedback loop that prevents overactivation of CD8+T cells and promotes memory formation.
Institut National de la Recherche Scientifique-Institut Armand-Frappier, Université du Québec, Laval, Quebec H7V 1B7, Canada.
Constance
C
Laroche-Lefebvre
Institut National de la Recherche Scientifique-Institut Armand-Frappier, Université du Québec, Laval, Quebec H7V 1B7, Canada.
Mitra
M
Yousefi
Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal, Quebec H1T 2M4, Canada; and.
Jean-François
JF
Daudelin
Institut National de la Recherche Scientifique-Institut Armand-Frappier, Université du Québec, Laval, Quebec H7V 1B7, Canada.
Tania
T
Charpentier
Institut National de la Recherche Scientifique-Institut Armand-Frappier, Université du Québec, Laval, Quebec H7V 1B7, Canada.
Esther
E
Tarrab
Laboratoire de Génomique Fonctionnelle de l'Université de Sherbrooke, Sherbrooke, Quebec J1E 4K8, Canada.
Roscoe
R
Klinck
Institut National de la Recherche Scientifique-Institut Armand-Frappier, Université du Québec, Laval, Quebec H7V 1B7, Canada.
Alain
0000-0002-7913-871X
A
Lamarre
Maisonneuve-Rosemont Hospital Research Centre, University of Montreal, Montreal, Quebec H1T 2M4, Canada; and.
Nathalie
N
Labrecque
Institut National de la Recherche Scientifique-Institut Armand-Frappier, Université du Québec, Laval, Quebec H7V 1B7, Canada.
Simona
S
Stäger
Institut National de la Recherche Scientifique-Institut Armand-Frappier, Université du Québec, Laval, Quebec H7V 1B7, Canada; pascale.duplay@iaf.inrs.ca.
Pascale
P
Duplay
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D002454:Cell Differentiation; D002470:Cell Survival; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D007156:Immunologic Memory; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D015398:Signal Transduction; D014615:Vaccinia / Q000276:immunology*; D014777:Virus Diseases / Q000276:immunology*
D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C489561:Dok1 protein, mouse; C498444:Dok2 protein, mouse; D010750:Phosphoproteins; D016601:RNA-Binding Proteins; D016693:Receptors, Antigen, T-Cell, alpha-beta