Friday, June 12, 2015

Systemic distribution of common origin T cell clones after skin immunization

Rapid memory to antigenic challenge is a fundamental feature of adaptive immune system. Accurate detection of antigen-specific T cells would play a major role in uncovering the mechanism leading to memory formation.

Thus far the most widely used technique to detect and track antigen-specific T cells was MHC-(or HLA) tetramer technology, developed in late 90s. However, this method is only optimal in tracking a limited number of antigen-specific T cells.

More recently new method of antigen-specific T cells tracking has started to be rapidly adopted by both academic and industry researchers. This new method is using HTS sequencing of TCR Vβ CDR3 regions that is unique to each clone. This method allows massive parallel tracking of T cell clones involved in immune response to tumors or immunization.

In this regard, this new paper in Nature Medicine has provided results based on tracking of T cell clones after skin immunization using TCR Vβ CDR3 sequencing data developed by Adaptive Biotechnologies. Of note, many recent high profile research articles published in top journals have used services and technologies developed by teams at Adaptive Biotechnologies. Here, the authors showed that clonal composition of skin and LN-derived T cells expanded after skin immunization were very similar, implying common origin.    

First, the authors showed that skin immunization induced accumulation of identical TCR Vβ CDR3 T cell clones in both local and distant skin tissue (TRM), as well as in draining and distal LNs (TCM). T cell frequency is measured as # of Vβ CDR3 copies per 400ng of genomic DNA.

Next, the authors showed that repeated immunization dramatically increased the frequency of TRM clones in the skin relative to its abundance in LNs. However, LNs still contained larger reservoir of different T cell clones that expanded after skin immunization.

Finally, using parabiosis model, the authors showed that skin-associated TRM (sedentary) cells provided rapid response to antigenic challenge compared to LN-associated TCM (migratory T cells).  However, for some reason, the magnitude of secondary response of TRM in distal skin tissue of sensitized mouse was less compared to its response in local sensitized tissue. This contradict their earlier data in Fig 1 where both local and distal tissues contain equal frequency of specific T cell clones expanded after skin immunization.

In summary, this new method may allow more efficient tracking of T cells expanded in response to antigen of interest. One caveat of this approach, of course, is the fact that there is no way to know for sure whether expanded T cell clones are indeed antigen-specific. Another important finding in this paper is the fact that T cell clones sampled from the blood after immunization showed no clonotypic resembles to clones found in skin or LN. This may indicate that experiments on blood (PBMC)-derived T cells may not provide an accurate picture of antigen-specific T cell response to antigens after skin immunization.

David Usharauli

No comments:

Post a Comment