Monthly Archives: May, 2015

B cells: from black and white to color set

B cells are part of adaptive immune system. They secret antibodies (IgM, IgG, IgA, IgE) and can present processed antigens to CD4 T cells.  However, beyond these functions, nothing much is known about B cells.

Studies on CD4 helper T cells, on the other hand, has uncovered and characterized multiple individual subsets ranging from Th1 to Th17.

Still, occasionally, one can come across of new paper in top journals (weird!) describing some new role of B cells that do not fit into current paradigm. Such example, for example, includes GM-CSF producing IRA B cells. In addition, there are plenty reports of IL-10 producing B cells involved in T cell suppression. Usually, immunologists would say “that’s weird” and then forget about it.

So why are research on B cells lagging so far behind the T cell’s studies?

One explanation has to do with the fact that unlike T cells, B cells do not survive well in an in vitro culture. One can re-stimulate T cells in vitro over and over again and they will still continue to expand (this is how originally Th1 and Th2 clones were derived). However, culture conditions developed for B cells thus far stimulate them to develop into short-term antibody-secreting cells (plasmablasts or  plasma cells) which finally will die, usually within 2 weeks of initiation of B cell culture. There is one report describing culture condition where the authors were able to maintain plasma cells for 60 days in vitro. But plasma cells are not B cells.

The real issue with B cells studies is the fact that we actually do not know how B cells survive in vivo. We don’t know what are the combination of stromal cells or cytokines that can provide tonic, survival signals to B cells. We don’t even know what is the role of surface IgM receptors in B cells survival in vivo.

Basically, we have an incomplete view of B cells biology. I think time has come to go back and re-evaluate our models for B cells. Without conceptual progress in B cells biology we will be just scratching our heads every time we hear some new research describing novel non-conventional B cell function.

posted by David Usharauli

How T cells interpret signaling delivered through chimeric antigen receptor (CAR)

Recently chimeric antigen receptor (CAR)-transduced T cell-based immunotherapy made headlines around the globe. Human trials conducted mostly against B cell-derived malignancies showed extraordinary medical benefits in large percentage of treated patients by extending their disease-free episodes for several years.

Below is a diagram of CAR molecule borrowed from Juno Therapeutics’ home page. Juno is one out of several biotech/pharma companies leading this field. As shown here, it is clear that current CAR construct contains several sub-signaling pathways (CD3zeta, CD28, etc).

 

Colors

Now, people who are familiar with basic immunology would notice that CAR construct artificially combines two principally distinct signaling pathways commonly known as signal 1 (CD3zeta) and signal 2 (CD28, etc). It is believed that such combination of two signaling pathways increases CAR T cells vitality and effector differentiation.

I would like to remind the readers that two-signaling model of T cell activation was introduced to account for tolerance towards self-antigens. It is thought to operate a kind of fail-safe mechanism to discriminate between self and nonself antigens. Since vast majority of nonself antigens would carry other attributes of “foreignness”, 2nd signal would be selectively available to nonself-specific T cells, but rarely to self-specific T cells.

Separation of signal 1 and signal 2 in T cells had to have some biological significance on how T cells interpret incoming signaling. This is especially critical for generation of long-term memory since unlike short-term immune response, memory cells with self-renewal potential could clearly cause long-term damage to the host’s tissue when inappropriately activated.

In my opinion, this is why innate cells, including NK cells, in most part, lack truly long-term memory potential. Innate cells are typically signal 1-only cells, meaning they could get fully activated after receiving specific signal 1. However, absence of memory formation among innate cells ensures that they would not go on and continue to damage host’s tissue once they are activated.

So, I can visualize similarities between how innate cells interpret activation signaling and CAR signaling in T cells. Absence of spatio-temporal separation of two signaling pathways in CAR-T cells may affect their memory differentiation potential, essentially transforming CAR-T cells into signal-1-only cells. If this model is correct, persistence and self-renewal potential of CAR-T cells in the hosts will be drastically reduced compared to normal memory T cells. Practically this could translate into diminished long-term medical benefits.

posted by David Usharauli

Paradox of post-publication citation

Publication records are one of the objective criterion one can use to assess scientist’s value. Of course, every scientist has a dream and desire to publish in top journals such as Nature or Science with impact factors 25 and higher .

However, absolute majority of research articles end up in society-sponsored journals. For example, Journal of Immunology, with impact factor between 3-5, is considered to be a “staple” journal in immunology. Scientist can publish his/her research article in Journal of Immunology and still feel “proud” of it.

Sure, there is enormous difference between Nature and Science and Journal of Immunology. First of all, it has to do with the branding. Both Nature and Science have huge reputation. People naturally assume that articles published there are of higher quality and reliable and indeed, on average it is absolutely true.

However, there is paradox with the regard of post-publication citations or referencing. I have frequently witnessed the fact that when scientists are presenting their work at research seminars or at scientific conferences, they are consistently citing or referring to any earlier studies as if totally equal, i.e. independent whether the referred studies were originally published in Nature, Science or Journal of Immunology (or PNAS).

In other words their confidence in reliability and quality of research results from Nature or Journal of Immunology are equal.

Logically, if you cite article from Journal of Immunology or Nature as if equal, then you accept that these journals publish equivalently valuable research results.

If so, then why are scientists still eager to publish in Nature or Science? I don’t know, that’s why it is a paradox.

posted by David Usharauli