| Abstract |
Tolerance induction of T cells in the periphery which is mediated through mechanisms that include anergy induction, immune deviation, activation induced cell death and dominant regulation by Tregs; protects host from adverse immune responses and autoimmunity. TNF is a multipotent cytokine which has drawn research attention due to both proinflammatory and immunosuppressive responses that is can mediate as well as its implication in mechanisms of peripheral tolerance.
In the system of self-tolerance of F531 Rag-/- and F531 TNF-/-Rag-/- animals that we studied, which bear CD8+T cells with a transgenic TCR capable of recognizing the nucleoprotein NP peptide of A/NT/60/68 virus, while at the same time they express the NP antigen as self peptide in all tissues, reduced number of peripheral CD8+T cells was recorded as compared to the control animals (F5 Rag-/- and F5TNF-/-Rag-/- accordingly), which denotes the clonal deletion of F5 cells after the in vivo encounter with their cognate antigen. In the absence of TNF, in the F531 TNF-/-Rag-/- animals, the number of peripheral CD8+T cells was slightly reduced as compared to the F531 Rag-/- animals, which implies a role of TNF in the peripheral clonal deletion. The F5 cells of both genotypes of the self-tolerance system, were positive for activation markers CD69 and CD44, which denotes their in vivo encounter with the antigen, while
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they did not produce INFγ nor did they proliferate in response to the in vitro rechallenge with the antigen, which denotes that these cells have been rendered anergic, a state that does not seem to be affected by TNF in this system.
In the control animals F5 Rag-/- and F5TNF-/-Rag-/- that we studied, where the CD8+T cells bear a transgenic TCR capable of recognizing the NP peptide, it was observed that in the absence of endogenous TNF a reduced number of peripheral CD8+T cells was recorded in the F5TNF-/-Rag-/- animals as compared to the F5 Rag-/- ones, an observation that implies the potential involvement of TNF in the reduction of peripheral CD8+T cells. In the same system, a distinctive separate peripheral population of CD8+T cells was recorded, which had a reduced expression level of the TCR receptor and this observation calls for more data regarding its generation. In addition, a percentage of the F5 cells were phenotypically characterized positive for the activation marker CD44 in the absence of TNF, the expression of which was absent from the control animals F5 Rag-/-. In the in vitro NP challenge assay, no difference was observed between the two genotypes in regard to their INFγ production, while the F5 cells of F5TNF-/-Rag-/- animals had a reduced proliferative ability as compared to the F5 Rag-/- ones, a fact that implies in accordance to previous results from the lab that TNF may affect the activation threshold of CD8+T cells, by means of lowering it. Finally, in the animals of this system, in vivo NP-antigen-specific cytotoxicity was recorded in the absence of TNF, 19 hours after the adoptive transfer of NP-loaded target cells, which does not seem to be mediated by granzyme B and is absent from control animals of F5 Rag-/- genotype.
The above data show that TNF may be implicated in the responses of cytotoxic CD8+T cells by lowering their activation threshold, as well as in the peripheral clonal deletion in the system of F531 Rag-/- and
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Ο ρόλος του ενδογενούς TNF σε in vivo αποκρίσεις περιφερικών CD8+T λεμφοκυττάρων διαγονιδιακών για TCR υποδοχέα
