Local guys know better

I am going to review three papers, one by one, published recently in journal Science, uncovering the role of tissue resident memory T cells in host defense against infection.

First paper from this pool came from Akiko Iwasaki' lab (1). Her lab has already published an initial observation in Nature in 2013. I would like to note that for past few years her lab's research output and authorship became more interesting and as a consequence more publishable in a highest rated journals. I do see some beneficial effect from Ruslan Medzhitov, her spouse.

However, I do wonder how papers with single first and single last authors is technically possible when considering vast amount of supplemental data.  

This study focus on role of memory CD4 T cells, generated after vaccination, to protect the host against lethal [viral] challenge.

The authors has used vaginal HSV-2 model in parabiotic mice to study the contribution of tissue resident and circulating CD4 memory T cells.

Parabiotic mice have circulation surgically co-joined. Probably not the nicest experience for mice.

First, the authors have immunized intravaginally mice [with either CD45.1 or CD45.2 genotype] with attenuated strain of HSV-2. Five weeks later, mice were surgically co-joined. Six week post parabiosis, the authors found that HSV-2 specific IFN-gamma secreting CD4 T cells from vaginal tissue were almost exclusively of host genotype despite equilibrium in lymphoid tissues.

Second, the authors conducted protection experiment in parabiotic pairs to determine the contribution of host or donor [circulating] memory CD4 cells in host defense against challenge with lethal dose of HSV-2. Interestingly, full protection was observed only in parabiotic pairs when tissue resident CD4 memory T cells were present in challenged partner. However, only half of the pairs were protected when no prior tissue resident CD4 memory T cells were present in challenged partner. In contrast, no protection was observed in naive parabiotic pairs, or when naive parabiotic partner challenged with lethal dose of HSV-2 was IFN-gamma receptor deficient, and when immunized partner of the parabiotic pair lacked CD4 T cells. In sum, this set of experiments showed that host tissue resident memory CD4 T cells display superior protection compared to re-circulating memory CD4 T cells and that IFN-gamma responsiveness played important role in this protection.

Finally, the authors showed that IFN-gamma dependent production of CCL5, CCL9 locally by tissue macrophages was important to retain tissue resident memory CD4 T cells ready to secrete high levels of IFN-gamma upon encounter with recall antigen, thus contributing to rapid host defense.

The importance of this study can not be overestimated. It showed that only immunization in tissues which serve as natural pathogen entries could provide full protection. This has implication to all current vaccination protocols where vaccinations has been done through skin immunization against infection with different natural entry routes (TB, Flu, HIV, etc).

David