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

1 comment:

  1. maybe deleting ctla-4, stop hiv replication
    source : 'AIDS virus can not replicate inside the mosquito, bed bug, flea, or
    other blood sucking insect and the lack of replication of HIV in arthropod
    cells due to lack of T4 antigen on cell surface'
    from google 'mosquito hiv'