Identifying cancer and pathogen-specific epitopes or TCRs may sound intuitive, but it is a futile approach. Diversity of T cell or B cell clones guarantees that the adaptive immune system will always have relevant clones to detect cancer or pathogen.   Epitopes have no meaning attached to them with one exception.  It is when the said epitope is self. Each body will have different sets of self-epitopes. Every self-epitopes relevant for host's survival are encoded in the thymus, and thymic Tregs are trained to prevent any T cell activity against those epitopes in the periphery. T ..read more

Molecular mimicry between microbial and host's antigens could contribute to autoimmunity but also to the protection against tumors through epitope cross-reactivity. A new study in journal Science indicates that those cross-reactive epitopes could come from viruses that infect endogenous microbial species.  In this study the authors made a surprising observation that only certain Enterococcus hirae microbial strains (E. hirae 13144 or IGR11) augmented anti-cancer effect in experimental cancer model.     Next, the authors showed that this biological activity was linked to one do ..read more

Here is the most recent paper that claims that they can do it. It was published in Science Translational Medicine. This is fairly respectable journal run by Science. This research group is so confident in their data that they even set up a new biotech company to commercialize their approach. I am going to examine how strong are their claims. Here is a short description what they did: they used a combination of specific nuclease (TALEN) and virus (AAV6) to insert a new promoter into Foxp3 gene in an in vitro activated T cells. They called these Tregs edTregs. insertion of MND promoter ..read more

Foxp3+ regulatory T cells (Tregs) are the most essential component of the immune system. No other cell population, taken singularly, have such an indispensable role in the proper functioning of the immune system. Tregs are known to inhibit inappropriate immune response against self-antigens, commensal microbiota or even nonself pathogens.  I strongly believe that data are very clear about it. So, when I see a well-designed research paper showing something contrary I immediately want to understand its details. Take this new paper from The Journal of Clinical Investigation (JCI) as an exam ..read more

Papers published in journal Science supposed to undergo thorough high-level vetting process. However, to err is human. Both reviewers and editors are humans and hence they frequently err, for the annoyance of scientists and for the joy of postdocs doing journal clubs.   Here is an example of a paper that squeezed through the cracks of the Science vetting process. It claims that peptides derived from certain commensal microbiota species cross-react with heart muscle protein, MYH6, causing autoimmune heart inflammation. It has a great Figure 1 showing that MYH6-specific TCR transgenic mice on ..read more

So far 3 different outcomes have been identified for developing T cells in the thymus: to develop into naive T cells, get deleted or become Foxp3+ Treg. Both deletion and Treg path require the presence of specific epitopes. However, how a given T cell decides between these pathways is not well understood.  Here is a new paper in PNAS that tries to tackle this question using the tetramer tracking approach. The authors are using PLP (brain-specific protein) as an endogenous antigen expressed in the thymus. Surprisingly both PLPWT and PLPKO mice showed near similar numbers of tetramer-positive ..read more

The most tumors express mutant epitopes that could be detected by T cells. According to current paradigm, CD4+ T cells provides help to CD8+ T cells that in turn attack tumors. As tumor cells ordinarily express class I recognized by CD8+ T cells but not class II molecules recognized by CD4+ T cells, primary focus on CD8+ T cell epitopes made a lot of sense. But what about CD4+ T cell 'help' to CD8 T cells?  Indeed, a new 'classically-done' immunology study from Robert Schreiber's lab clearly showed that irrespective class II expression, tumor cells must express both CD8+ and CD4+ T cell neo ..read more

The T cells expressing the transcription factor Foxp3 called regulatory T cells, abbreviated as Tregs, are the most important cell type in the immune system. Without them, the whole immune system goes haywire. As a result, the body simply dies in a very short time. The Tregs develop in the thymus and require two things: TCR signaling and IL-2. The thymus expresses a very diverse set of epitopes including that from peripheral tissues such as the pancreas or prostate. The high-affinity interaction between TCR and epitope/MHC II makes proto-Treg sensitive to local IL-2, a necessary step to compl ..read more

Recently journal Nature published a very thought-provoking study from Mark Davis' lab. In it, the authors have described the existence of a specialized population of CD8+ T cells that prevented auto-reactive CD4+ T cells from causing autoimmune brain inflammation (EAE) in mice, a laboratory model for human multiple sclerosis. Let's analyze what the study shows. Both Fig. 1 and Fig. 2 are rather superfluous as they simply show either time kinetics of CD4+, CD8+ and γδ+ T cells responses in the blood or CNS following autoantigen immunization (Fig. 1) or frequency of TCR clonal  distribution bas ..read more

The mouse strain, NOD, has been used to study the mechanism of type 1 diabetes (T1D). These mice spontaneously develop autoimmune diabetes though it is not clear how islet-specific T cells get activated. To track autoimmune T cell fate, TCR transgenic mice, BDC2.5XNOD, have been used. These mice harbor islet-specific TCR expressing T cells in high numbers that are easily monitored. A new study in PNAS did some experiments on BDC2.5XNOD mice to understand the initiation of autoimmunity. First, they showed that the NOD background showed increased gut wall barrier permeability by measuring the F ..read more