Tissue retention of antigen-specific resident memory T cells

In recent years research in memory T cell response showed that secondary response to peripheral antigen challenge is driven mostly by locally-residing, tissue resident memory T cells (T_RM). Such studies are important to understand how vaccines affect development of T_RM (previously, main focus was on memory T cells residing in lymphoid tissues, such as spleen and lymph nodes).

Few studies suggested that virus induced T_RM cells could migrate out and reside in tissues not directly affected by virus [i.e. Ag-independent manner]. However, immune response to different viruses can differ fundamentally from each other. For example, new report in Journal of Experimental Medicine (JEM) showed that skin infection with vaccinia virus (VacV, a benign relative of smallpox) instructs development and retention of local T_RM in an antigen-specific manner.

In mice, infection with VacV by skin scarification produces local infection and induction of virus antigen-specific T cell response is local as well.

Importantly, accumulation of CD8 T cells within infected tissue was indeed antigen-specific, and not driven by local virus-induced inflammation per se.

Secondary antigenic challenge confirmed that T_RM response was restricted to local tissue previously infected with virus carrying the same antigen.

In summary, this study showed that in case of VacV infection tissue retention of T_RM cells was antigen-dependent and occurred locally at the site of primary viral challenge.

David Usharauli

Hobit controls tissue residency of memory T cells

Tissue resident memory T cells, T_RM, represent newly recognized T cell population that play physiologically-relevant role in body's defense against reinfection. T_RM cells are local tissue surveyors and act as a first-line defense [alongside of innate immunity] against tissue invading pathogens. Beyond these information nothing much was known about T_RM cells.

Now, a new paper published in Science showed that transcription factor named Hobit is a master regulator of T_RM cell development.   

Using mouse HSV-1 model, the authors found that by day 30 post-infection, Hobit was selectively up-regulated in T_RM cells recovered from peripheral tissues, such as skin, but not in central lymphoid tissues such as spleen.

Using Hobit-KO T cells the authors were able to confirm that Hobit was indeed intimately involved in development of tissue-resident memory T_RM cells (memory stage, day 40+). Deficiency of another transcription factor, Blimp1, had an additive effect on T_RM cells formation when combined with Hobit deficiency. 

Interesting, Hobit, in combination with Blimp1, also controlled tissue residency of innate cells such NK and NKT cells.

In summary, this study revealed that transcription factor Hobit controls tissue residency of memory T cells, T_RM cells. These data should be considered in developing T cell-oriented vaccines, including cancer immunotherapy (one limitation of this study is that for some reason the authors failed to show actual virus protection data with the regard of Hobit or Hobit + Blimp1 DKO T cells. ).

David Usharauli 

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 (T_RM), as well as in draining and distal LNs (T_CM). 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 T_RM 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 T_RM (sedentary) cells provided rapid response to antigenic challenge compared to LN-associated T_CM (migratory T cells).  However, for some reason, the magnitude of secondary response of T_RM 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