AUTHOR=Prout Melanie Sarah , Kyle Ryan L. , Ronchese Franca , Le Gros Graham 

TITLE=IL-4 Is a Key Requirement for IL-4- and IL-4/IL-13-Expressing CD4 Th2 Subsets in Lung and Skin

JOURNAL=Frontiers in Immunology

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2018.01211

DOI=10.3389/fimmu.2018.01211

ISSN=1664-3224

ABSTRACT=<p>Although IL-4 is long associated with CD4 Th2 immune responses, its role in Th2 subset development in non-lymphoid tissues is less clear. We sought to better define IL-4’s role in CD4 Th2 responses by using transgenic mice that express a dual IL-4 AmCyan/IL-13 DsRed (IL-4AC/IL-13DR) fluorescent reporter on an IL-4-sufficient or IL-4-deficient background. Using primary Th2 immune response models against house dust mite or <italic>Nippostrongylus brasiliensis</italic> (<italic>Nb</italic>) allergens, we examined the requirement for IL-4 by each of the defined Th2 subsets in the antigen draining lymph node, skin, and lung tissues. In the lymph node, a CXCR5<sup>+</sup>PD-1<sup>+</sup> T follicular helper (Tfh) and a CXCR5<sup>lo</sup>PD-1<sup>lo</sup> Th2 subset could be detected that expressed only IL-4AC but no IL-13DR. The number of IL-4AC<sup>+</sup> Tfh cells was not affected by IL-4 deficiency whereas the number of IL-4AC<sup>+</sup> Th2 cells was significantly reduced. In the non-lymphoid dermal or lung tissues of allergen primed or <italic>Nb</italic>-infected mice, three strikingly distinct T cell subsets could be detected that were IL-4AC, or IL-4AC/IL-13DR, or IL-13DR CD4. The IL-4- and IL-4/IL-13-expressing subsets were significantly reduced in IL-4-deficient mice, while the numbers of IL-13-expressing CD4 T cells were not affected by IL-4 deficiency indicating that other factors can play a role in directing the development of this Th2 subtype. Taken together, these data indicate that the appearance of IL-4-expressing Tfh cells in the lymph node is not dependent on IL-4 while the appearance of IL-4-expressing Th2 subsets in the lymph node and IL-4, IL-4/IL-13-expressing Th2 subsets in skin and lung tissues of antigen primed mice is significantly IL-4 dependent.</p>