Transforming growth factor-beta suppresses the activation of CD8+ T-cells when naive but promotes their survival and function once antigen experienced: a two-faced impact on autoimmunity.
OBJECTIVE
Transforming growth factor-beta (TGF-beta) can exhibit strong immune suppression but has also been shown to promote T-cell growth. We investigated the differential effect of this cytokine on CD8(+) T-cells in autoimmunity and antiviral immunity.


METHODS
We used mouse models for virally induced type 1 diabetes in conjunction with transgenic systems enabling manipulation of TGF-beta expression or signaling in vivo.


RESULTS
Surprisingly, when expressed selectively in the pancreas, TGF-beta reduced apoptosis of differentiated autoreactive CD8(+) T-cells, favoring their expansion and infiltration of the islets. These results pointed to drastically opposite roles of TGF-beta on naïve compared with antigen-experienced/memory CD8(+) T-cells. Indeed, in the absence of functional TGF-beta signaling in T-cells, fast-onset type 1 diabetes caused by activation of naïve CD8(+) T-cells occurred faster, whereas slow-onset disease depending on accumulation and activation of antigen-experienced/memory CD8(+) T-cells was decreased. TGF-beta receptor-deficient CD8(+) T-cells showed enhanced activation and expansion after lymphocytic choriomeningitis virus infection in vivo but were more prone to apoptosis once antigen experienced and failed to survive as functional memory cells. In vitro, TGF-beta suppressed naïve CD8(+) T-cell activation and gamma-interferon production, whereas memory CD8(+) T-cells stimulated in the presence of TGF-beta showed enhanced survival and increased production of interleukin-17 in conjunction with gamma-interferon.


CONCLUSIONS
The effect of TGF-beta on CD8(+) T-cells is dependent on their differentiation status and activation history. These results highlight a novel aspect of the pleiotropic nature of TGF-beta and have implications for the design of immune therapies involving this cytokine.
Filippi
Christophe M
CM
La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
Juedes
Amy E
AE
Oldham
Janine E
JE
Ling
Ellie
E
Togher
Lisa
L
Peng
Yufeng
Y
Flavell
Richard A
RA
von Herrath
Matthias G
MG
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D015551:Autoimmunity / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D002470:Cell Survival / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D005434:Flow Cytometry; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D010179:Pancreas / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D016212:Transforming Growth Factor beta