Friday, January 15, 2016

CD4 T cells provide universal "help" to CD8 T cells via pathogen-tailored DCs

Ordinarily [but not always] naive CD8 T cells require "help" from CD4 T cells to undergo full differentiation and to develop into memory. Such CD4 T cell help is provided via so called "licensed" antigen-presenting cells, DCs. In a simple scenario, when pathogen invades tissue, local DCs will pick up its antigens and present them to both CD4 and CD8 T cells. In turn, activated antigen-specific CD4 T cell "licenses" the same DCs to up-regulate or secrete necessary molecules to complete priming of naive CD8 T cells (I am going to use terms "help and "license" interchangeably).

This simple model is complicated by fact those "licensing" molecules for CD8 T cells differ depending on pathogens. The most well described "helps" include IL-12, IL-15 or type I IFNs. So, how CD4 T cells are able to deliver so many different licensing signals?  

Apparently, CD4 T cells don't. According to new paper published in Cell Reports, CD4 T cells simply amplifies pre-existing pathogen-tailored signals within DCs. Lets see if data are convincing (note, this paper was under review process for > 2 years)

Initially, the authors confirmed that CD8 T cell priming/expansion during viral infection, HSV-1, required presence of CD4 T cells, MHC II, CD40L or CD40.

Next, the authors showed that CD8 T cells priming/expansion during HSV-1 infection required signaling via either IFNαR or IL-15.
Experiments with BM chimeras, IL-15KO:CD11cDTR and IFNαRKO:CD11cDTR, revealed that DCs-specific expression of IFNαR and IL-15 were required for CD8 T cell priming during HSV-1 infection.

However, production of IL-15 by DCs in response to IFNα also required presence of CD4 T cells.

In fact, ex vivo stimulation of CD8α+ DCs with IFNα and αCD40-mimetic (as a surrogate for CD4 T cell help) showed that CD4 T cell "help" amplified IL-15 induced by innate [viral-induced] IFNα (since αCD40-mimetic alone had no effect). However, it is not clear whether αCD40-mimetic could fully recapitulate CD4 T cell function. So, this requires additional tests.

Dominant role of innate signaling in determining the nature of CD4 T cell "help" was revealed in experiments in which mice were challenged with cell-associated OVA in combination with LPS or Poly(I:C). In presence of LPS, "help" was IL-12 dependent, while in presence of Poly(I:C), "help" was IL-15 dependent.

In summary, the conclusion of this study, according to the authors, is that CD4 T cells simply amplify pathogen-tailored innate signals already generated within DCs, rather than proving unique maturation signals. My interpretation of these results is not very different from earlier models. I don't think that anyone claimed that CD4 T cell "help" and innate signals were completely interchangeable. For me, "licensing" and in this case "amplification" are very same concepts. For me, more important question is how those CD4 T cells that deliver "help" are getting activated in first place (basically, who primes the "primers").

David Usharauli


  1. Enjoyed reading this paper, myself. Definitely in my top 3 favs of 2015. Thing that tickled my fancy was bi-fold:

    1. What we've been "conditioned" to believe from textbooks and literature about the co-synapse of CD4s and CD8s on the same APC is just half the story clearly shown in this paper. Osborne/Goldsby sections in Kuby have told us that it is the same DCs that do the priming.. but clearly there's this spatial segregation between the two lymphocyte populations.

    2. In addition to what you put forth (who primes those CD4s in the first place), I've also wondered what happens to the DCs in the process? Are the DCs themselves coercing in the information exchange. Do they hold the one piece of puzzle already and are given the other from CD4s, which they carry to CD8s as a photoID? or is it that they are simply playing tag? How much of the CD4 synapse experience changes the DCs, beyond just the messengers?

    I wonder. Truly, the sexiest story of 2015 in my book.

  2. Thanks for comments.

    Regarding 1st point. It is true that the same DC is needed to prime naive CD8 T cells but there is no need for both CD4 and CD8 T cells to engage that DCs at the same time. Indeed there's this spatial/temporary segregation between priming events of the two (CD4/CD8) lymphocyte populations (usually first CD4/DC interaction, followed by CD8/DC contact). In fact, such segregation was originally proposed and shown by Polly Matzinger's group in late 90s.

    Regarding 2nd point. This is more interesting and more complex question. Exactly, the real Q is what type of "information exchange" is going on between DC and T cells. We know very little about this process (just MHC+antigen, co-stimulation or cytokines, if we are lucky). But what about the role of tissue, Tregs or innate cells play in this process?