Regulatory T cells with a single TCR specificity prevent lethal autoimmunity

Foxp3+ regulatory T cells, Tregs, prevent autoimmunity and their total or partial defects can cause lethal or variable autoimmunity. For most part, endogenous ligands recognized by Tregs are not known.

Based on data derived from artificial transgenic models it is suggested that development and maintenance of naturally derived Tregs could be antigen-specific, though it is not known how diverse Treg TCR repertoire should be to keep auto-reactive T cells in check.

To answer this question, Rudensky's research group conducted series of experiment on transgenic mice (G113TgFoxp3^YFP-CreTcra^FL/FL mice) which harbor normal repertoire of conventional T cells but where "all" naturally developed Treg cells would express single TCR specificity (derived from Vβ6+Vα2+ G113 TCR).

Surprisingly, unlike control mice (which did not survive past 4 wk of age), 50% of G113TgFoxp3^YFP-CreTcra^FL/FL mice survived to 4 mo of age (the end point of the experiment) though all of them displayed "visible evidence of significant autoimmunity".

So what does this result tell us? These are quite unexpected results. It would be highly unusual to imagine that a single antigen and single Treg specificity could be sufficient to prevent lethal autoimmunity in 50% of mice. We don't even know the source of the endogenous antigen G113 TCR supposed to recognize.

I personally would rather focus on technical aspect of this result: how robust is TCR modification in G113TgFoxp3^YFP-CreTcra^FL/FL mice? Maybe there is still "leakage" of endogenous TCRalpha chains? I wonder about this because of "50% data". Maybe in those 50% surviving mice Tregs were able to assemble TCR with endogenous TCRalphas?

David Usharauli  

Tumor immunotherapy: 1 year at a time

Tumor immunotherapy is both an old and new idea. Whenever there is a new discovery in immunology, people usually are asking 3 questions: can it cure HIV, cancer or allergy?

Recently, a promise for successful immunotherapeutic approach to cancer treatment was boosted by clinical introduction of anti-CTLA4 and anti-PDL1 humanized antibodies. These antibodies target and exploit the natural inhibitory checkpoints in T cell activation program relevant for natural tolerance process to self or food antigens. There is another approach as well, called CAR-T technology, that I will review later.

Still, the actual, long-term benefits of current immunotherapeutic approaches are debatable. Here is one example. This is a Science paper. The senior author on this paper is Steven Rosenberg. This is a guy who actually has started clinical immunotherapy with IL-2 in 1980's.

This paper describes a single patient's personalized tumor immunotherapy protocol. Initially, the authors sequenced a metastatic tumor obtained from resected lung tissue and found 26 mutations. Next, they have prepared 3 different tandem minigene constructs (8-9 mutations each), transfected them in autologous antigen-presenting cells and run ex vivo TIL (tumor-infiltrated lymphocytes) activation assay. Only one construct, TMG-1, showed TIL reactivity.

Next, from this tandem minegene construct (that contained 9 mutant minigens), the authors synthesized 9 individual minigene constructs with each containing reversion of one mutation back to wild-type sequence, so to permit detection TIL specificity by antigen elimination. Interestingly, TIL's reactivity was abolished when erbb2 interacting protein was reverted to wild-type sequence. 

In addition, TIL's tumor reactivity was localized in CD4 T cell subset and was made up mostly of Vbeta22+ CD4 T cells. 

Thus this patient's TIL (CD4 T cells) specificity was directed towards one mutation in erbb2ip.

Next, the authors has expanded patient's TIL in vitro and injected back 42.4 billion TIL (25% Vbeta22+) into patient. This adoptive transfer of tumor specific TIL produced >1 year tumor burden stabilization and regression of metastatic tumor in liver and lung.

After 1.5 year from the initial TIL transfer, tumor re-emerged, so the patient was re-injected with in vitro expanded 100 billion tumor specific Vbeta22+ TIL and again such transfer produced additional >6 months stabilization and regression of tumor metastasis.

It appears that the difference between this graph and Fig. 2 D has to do with the fact that the authors measured only those tumor lesions which were present during both treatments.

What we have learned from this study? First, tumor in this case did express neo-antigen detected by CD4 T cells. Second, in vitro expansion of tumor-specific TILs and their adoptive transfer back into patient yielded >1 year (after single transfer) and in total >2 years (after 2nd transfer) of tumor burden stabilization and metastatic regression. Third, this approach, however, did not provide a long-lasting tumor-protective effect, despite presence of transferred tumor-specific CD4 T cells.

Does it mean that TIL approach is not viable in a long run? Why were billions of tumor-specific T cells not able to eliminate tumor? Because of inhibitory milieu at tumor sites? Were they terminally-differentiated T cells lacking self-renewal properties? It seems that tumor was able to escape CD4 T cell control despite the fact it still continued to express neo-antigen. How? 

David Usharauli