Thread by @casanova_lab

1/ We are excited to share exciting news about human IL-23 in #ScienceImmunology (science.org/doi/10.1126/sc…).

2/ The early 2000s discovery of IL-23 and IL-23R was associated with the characterization of TH17 cells as distinct T-cell lineage, different from TH1 / TH2 cells (nature.com/articles/natur…).

3/ In this paradigm, IL-12 is the IFN--inducing signature cytokine, whereas IL-23 is the IL-17-inducing signature cytokine (nature.com/articles/nm.38…).

4/ However, in 2018, we reported two siblings with inherited IL-23R deficiency and surprisingly, mycobacterial disease in @SciImmunology (science.org/doi/10.1126/sc…).

5/ In the same issue of @SciImmunology, we reported that homozygosity for P1104A TYK2 selectively impairs cellular responses to IL-23 and underlies mycobacterial disease (science.org/doi/10.1126/sc…).

6/ These findings paradoxically suggested that contrary to the IL-12/TH1 and IL-23/TH17 paradigm, human IL-23 is required for optimal IFN--dependent immunity to mycobacteria, but redundant for optimal IL-17-dependent immunity to C. albicans (science.org/doi/10.1126/sc…).

7/ Here, in @ SciImmunology again, (science.org/doi/10.1126/sc…) we report an in-depth molecular, immunological, and clinical analysis of six patients from four kindreds with IL-23R deficiency. All of them had mycobacterial disease, while only two had mild candidiasis.

8/ We show that the development of C. albicans–specific memory CD4+ T cells is preserved in IL-23R–deficient patients and that IL-23 induces IL-17A only in MAIT cells, possibly accounting for the incomplete penetrance of candidiasis in patients unresponsive to IL-23.

9/ By contrast, IL-23 is required for both baseline and IL-23-inducible IFN- immunity in both V2  T and MAIT cells, likely contributing to the much higher penetrance of mycobacterial disease in these patients.

10/ These findings are consistent with our recent report that impaired IL-23 signaling is the core mechanism of mycobacterial disease in patients with all forms of inherited TYK2 deficiency (doi.org/10.1084/jem.20…).

11/ Overall, our findings suggest that human IL-12 and IL-23 are functionally very closely related, via their induction of IFN-γ.

12/ These findings conflict with the classical TH1/TH17 paradigm established in mice, further suggesting that mouse and human immunology should be reconsidered through the lens of genetics (doi.org/10.1146/annure…).

13/ These findings further suggest that the clinical efficacy of IL-23 blockers may not be related to their impact on IL17 immunity – but rather to its impact on IFN-… (nature.com/articles/nri37…)

14/ Thanks to all co-authors and co-investigators involved all across the world including @PhilippotQ @MasatoOgishi, @Jonathan_Bohlen, @AriasAAS, @Marta_MartinF, @clementco_6, @ManaMomenilandi, @Jrosain, @ryangrui, @ALNeehus, @LevyRomain, @zhangpeng1202, @CarlosArangoFr1...

15/ @pelham_simon, @Boisson_Bebo, @_nicomarr, @SatoshiOkada3, @AurelieCobat, @BogunovicLab, @LaurentAbel4, @DrCindyMa, @stutangye, @BeziatV, @sallustolab, @BoissonDupuis, @BustamanteJaci1, @casanova_lab, @anne_puel, and many other not yet on twitter.