CD8+ T-cell-mediated killing of donor dendritic cells prevents alloreactive T helper type-2 responses in vivo.
Accumulating evidence indicates that, in absence of CD8+ T-cell activation, CD4+ T-cell-mediated allograft rejection is associated with a dominant Th2-cell response and eosinophil infiltrates. In this study, we analyzed the mechanisms by which CD8+ T cells regulate alloreactive CD4+ T-cell priming and differentiation into interleukin 4 (IL-4)-producing cells. We showed that interferon gamma (IFN-gamma) production by CD8+ T cells was dispensable for the inhibition of Th2-cell development, as well as tissue eosinophilia and type 2 cytokine production in the rejected grafts. Since we noticed that CD8+ T cells not only suppressed Th2 differentiation, but also down-modulated the overall priming of alloreactive CD4+ T cells, we evaluated whether CD8+ T cells act by limiting the accumulation of donor-derived dendritic cells (DCs) in lymph nodes. We found that indeed, alloreactive CD8+ T cells rapidly eliminated allogeneic DCs from T-cell areas of draining lymph nodes, through a perforin-dependent mechanism. Thus, our data demonstrate that cytotoxic T lymphocyte (CTL)-mediated clearance of allogeneic DCs is a negative feedback mechanism that limits the duration of alloantigen presentation in draining lymph nodes, thereby modulating the amplitude and polarization of the primary alloreactive CD4+ T-cell responses.
Laffont
Sophie
S
INSERM U563, CHU Purpan, Place du Dr Baylac, 31 300 Toulouse, France.
Coudert
Jérôme D
JD
Garidou
Lucile
L
Delpy
Laurent
L
Wiedemann
Aurélie
A
Demur
Cécile
C
Coureau
Christiane
C
Guéry
Jean-Charles
JC
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D002465:Cell Movement; D017690:Cell Transplantation; D003713:Dendritic Cells / Q000166:cytology*; D015536:Down-Regulation; D004802:Eosinophilia / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008207:Lymphatic Metastasis; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018418:Th2 Cells
D015847:Interleukin-4; D007371:Interferon-gamma