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. 2015 Nov 1;195(9):4257-4263.
doi: 10.4049/jimmunol.1402584. Epub 2015 Sep 16.

A Stromal Cell Niche for Human and Mouse Type 3 Innate Lymphoid Cells

Kerim Hoorweg #  1 , Priyanka Narang #  2 , Zhi Li  2 , Anne Thuery  2 , Natalie Papazian  1 , David R Withers  3 , Mark C Coles  2 , Tom Cupedo  1
Affiliations

A Stromal Cell Niche for Human and Mouse Type 3 Innate Lymphoid Cells

Kerim Hoorweg et al. J Immunol. .

Abstract

Adaptive immunity critically depends on the functional compartmentalization of secondary lymphoid organs. Mesenchymal stromal cells create and maintain specialized niches that support survival, activation, and expansion of T and B cells, and integrated analysis of lymphocytes and their niche has been instrumental in understanding adaptive immunity. Lymphoid organs are also home to type 3 innate lymphoid cells (ILC3), innate effector cells essential for barrier immunity. However, a specialized stromal niche for ILC3 has not been identified. A novel lineage-tracing approach now identifies a subset of murine fetal lymphoid tissue organizer cells that gives rise exclusively to adult marginal reticular cells. Moreover, both cell types are conserved from mice to humans and colocalize with ILC3 in secondary lymphoid tissues throughout life. In sum, we provide evidence that fetal stromal organizers give rise to adult marginal reticular cells and form a dedicated stromal niche for innate ILC3 in adaptive lymphoid organs.

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Figures

Figure 1
Figure 1. Stromal LTo cells in human fetal lymph nodes
Fetal human lymph nodes and mesenteries were analyzed for presence of cells resembling murine LTo cells. (a) Expression of VCAM-1, ICAM-1, LTβR and RANKL on CD45-CD31− stromal cells from first trimester mesenteries. (n=3; age range: 8-10 weeks gestation) (b) Expression of VCAM-1, ICAM-1 and LTβR on CD45−CD31− stromal cells dissected from second trimester lymph nodes. (n=5; age range: 8-10 weeks gestation) (c) Localization of VCAM-1+ and RANKL+ stromal cells directly underneath the Podoplanin expressing subcapsular sinus (magnification 100x) (d) Co-localization of Rorγt+ cells and RANKL+ cells in fetal lymph nodes (magnification 100x/250x) (n=5) (e) Transcript analysis by qPCR of CD45−CD31− RANKL+ and RANKL− stromal cells purified from second trimester lymph nodes (n=8) compared to total CD45+ cells (n=4). (c-e: second trimester; age range 15-22 weeks gestation)
Figure 2
Figure 2. Stromal organizer cells in fetal human spleen
Fetal human spleens were analyzed for the presence of putative stromal organizer cells (a) Appearance of perivascular lymphocyte clusters in fetal human spleens of 15 to 18 weeks gestation. (b) Appearance of MAdCAM-1+ cells in developing white pulp at week 18 (c) MAdCAM-1+Lyve-1−CD31− stromal cells in spleens of 18 weeks gestation. (d) Flow cytometric analysis of fetal spleens showing the appearance of CD45−CD31− MAdCAM-1+ stromal cells (n=3).
Figure 3
Figure 3. LTo and ILC in human fetal spleen
(a) Comparison of transcript levels for LTBR, CXCL13, CCL21 and CCL19 in CD45−CD31−MAdCAM-1− and MAdCAM-1+ stromal cells as well as total CD45+ cells from fetal human spleens. (n>3; age 14-22 weeks) (b) Localization of Rorγt+CD3− ILC3 in fetal spleens (arrowheads indicate Rorγt+ cells, (magnification 100x/250x) (n=3; age 14-22 weeks) (c) Phenotype of fetal splenic Lineage−CD117+CD127+Rorγt+ ILC3 compared to fetal splenic CD56+CD3− NK cells (n=3; age 14-22 weeks).
Figure 4
Figure 4. Stromal MRC in adult human lymph nodes
Human non-inflamed adult lymph nodes were analyzed for presence of MRC. (a) Stromal cells expressing VCAM-1 and MAdCAM-1 in adult human lymph nodes. (b) Stromal cells expressing RANKL in adult human lymph nodes (magnification 100x/250x). (c) CXCL13 expression by stromal cells at the follicle boundary (magnification 100x/250x). (d) Roryt+ cells in the inter-follicular areas of adult human lymph nodes co-localize with RANKL+ stromal cells (arrowheads indicate Rorγt+ cells, magnification 100x) (n>4).
Figure 5
Figure 5. Lineage tracing of fetal LTo cells
(a) Condensation of YFP+ mesenchyme in the jugular lymph sac (jls) region of embryonic IL7-cre+ Rosa26eYFP+ mice at the indicated embryonic age in days (n=3). (b) Flow cytometric analysis of CD45−CD31− stromal cells from E16.5 MLN from IL7-cre+ Rosa26eYFP+ mice (n=2). (c) No co-expression of VCAM-1 and Lyve-1 in lymph nodes from adult IL7-cre+ Rosa26eYFP+ mice. (d) Lymph nodes from adult IL7-cre+ Rosa26eYFP+ mice show co-expression of YFP and Lyve-1 and of YFP and VCAM-1 or gp38. CD35+ FDC do not express YFP (n=5). (e) representative flow cytometry plot of CD45−CD31−gp38+ lymph nodes from adult IL7-cre+ Rosa26eYFP+ mice labelled with MAdCAM-1 (f) Transcript analysis of sorted CD45−CD31−gp38+YFP+ and YFP− stromal cells and total CD45+ cells from adult lymph nodes of IL7-cre+ Rosa26eYFP+ mice (n=2-4).
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