Saturday, September 19, 2015

CTLA-4 deletion during adulthood leads to a paradoxical resistance to autoimmune disease

CTLA-4 is a T cell inhibitory molecule that competes with CD28 for binding CD80/CD86 co-stimulatory molecules on dendritic cells. It is believed that CTLA-4 functions as a "brake" for T cell activation, a function also referred as a "checkpoint" inhibition. Total genetic deficiency of CTLA-4 or just on Foxp3+ regulatory T cells leads to early onset wasting syndrome and fatal autoimmune diseases. This what we knew up to now. 

However, a new study in Journal of Experimental Medicine, has put upside down the whole concept of "checkpoint" inhibition for CTLA-4. Using genetically-modified mouse models, the authors reported that total or Foxp3+ regulatory T cell-specific conditional deficiency of CTLA-4 in adult mice leads to protection rather than acceleration of autoimmune disease.   

First, the authors have generated mouse model that allowed conditional deletion of total or Foxp3+ Treg-specific CTLA4 (UBCCre/ERT2+ Ctla4fl/fl and Foxp3eGFP/Cre/ERT2+ Ctla4fl/fl).

Next, the authors treated mice with tamoxifen to activate Cre recombinase and delete CTLA4 and challenged mice with myelin self-peptide to induce experimental autoimmune encephalitis (EAE). Surprisingly and contrary to widely held belief, adult mice conditionally deficient for CTLA-4 were highly resistance for EAE induction.

Similar resistance for EAE induction was observed with mice with adult-onset CTLA4 deletion specifically on Foxp3+ regulatory T cells.

To rule out any off-target effect of CTLA-4 deletion, the authors transferred T cells from UBCCre/ERT2+ Ctla4fl/fl into T-deficient hosts and then challenged with tamoxifen and myelin self-peptide. Here too, deletion of CTLA4 on mature T cells protected against EAE. Moreover, adoptive transfer of purified, naive Foxp3- T cells from UBCCre/ERT2+ Ctla4fl/fl mice or transgenic 2D2 T cells specific for myelin self-peptide on UBCCre/ERT2+ Ctla4fl/fl background were capable of inducing EAE, implying that T cells were not inherently incapable of inducing EAE but were actively suppressed by absence of CTLA-4 on Foxp3+ regulatory T cells.

Additional experiments revealed that CTLA-4 deletion in adulthood skewed T cells response towards IL-10 production in UBCCre/ERT2+ Ctla4fl/fl mice.

Finally, the authors showed that CTLA-4 deletion during adulthood did not modify anti-tumor response against MC38 colon adenocarcinoma cells in UBCCre/ERT2+ Ctla4fl/fl mice.

In summary, these results question the assumption that inhibition of CTLA-4 function during adulthood would lead to autoimmune disease. Based on these results, it is unclear how anti-CTLA4 antibody therapy provides benefits during tumor immunotherapy. It maybe the difference between mouse and human immune system or it could be that mechanism of action of anti-CTLA4 antibody is not a "checkpoint inhibition" after all.

David Usharauli

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