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-15^KO:CD11c^DTR and IFNαR^KO:CD11c^DTR, 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

Steady-state IL-12p70-producing CD103+ DCs control magnitude of type II immunity

In my previous post I reviewed the role of microbiota and MyD88/TRIF pathway in CD103⁺ DC-derived TGF-β dependent IgA production. In the following review I will continue analyzing immunobiology of CD103⁺ DCs. Surprisingly, new paper published in JEM claims that CD103+ DCs naturally producing biologically active IL-12p70 restrain type II immunity during worm infection.

I have done some work on IL-12, so I was curious to review this paper. So lets begin. I will only show the data that I believe are relevant for the story. In first set of experiments, the authors showed that Batf3 ^-/- mice that lack CD103⁺ DCs have exaggerated type II response to S. mansoni eggs and worm infection itself (a typical Th2 trigger).

Similar exaggerated Th2 response were observed in Batf3 ^-/- mice infected with another Th2 trigger H. polygyrus. 

More importantly, Batf3 ^-/- mice showed increased resistance to H. polygyrus infection. 

To understand how Batf3-dependent CD103⁺ DCs influenced Th2 response, the authors analysed expression of IL-12, a cytokine known for its role in inhibiting Th2 response. Indeed, Batf3-dependent CD103⁺ DCs were main producers of steady-state IL-12 as measured by YFP expression under p40 promoter (p40 is a β chain of heterodimeric IL-12p70).

Finally, using bone marrow chimera, the authors showed that lack of biologically active IL-12 (IL-12p70) derived from Batf3-dependent CD103⁺ DCs was indeed responsible for exaggerated [and protective] Th2 response of Batf3^-/- mice to H. polygyrus.

Of note, in separate set of experiments with germ-free and MyD88/TRIF DKO mice, the authors claim that Batf3-dependent CD103⁺ DCs were producing biologically active IL-12p70 independently of microbiota or TLR signaling. However, in contrast to YFP expression, flow staining pattern with antibody against p40 revealed little staining of IL-12p40 in CD103⁺ DCs from any of the mice analyzed. So, if not the data with IL-12p35^-/-/Batf3^-/- BM chimera, I would have dismissed this whole study as an artifact (to be convincing the authors need to show these results with p40-YFP mice on GF and MyD88/TRIF background).

In summary, this study suggests that Batf3-dependent CD103⁺ DC-derived IL-12p70 influences magnitude of type II immunity.

David Usharauli