A human immune system mouse model with robust lymph node development

Yan Li; Guillemette Masse-Ranson; Zacarias Garcia; Timothée Bruel; Ayrin Kök; Helene Strick-Marchand; Gregory Jouvion; Nicolas Serafini; Ai Ing Lim; Mathilde Dusseaux; Thierry Hieu; Franck Bourgade; Antoine Toubert; Daniela Finke; Olivier Schwartz; Philippe Bousso; Hugo Mouquet; James P Di Santo

doi:10.1038/s41592-018-0071-6

A human immune system mouse model with robust lymph node development

Nat Methods. 2018 Aug;15(8):623-630. doi: 10.1038/s41592-018-0071-6. Epub 2018 Jul 31.

Authors

Yan Li^{1

2}, Guillemette Masse-Ranson^{1

2

3}, Zacarias Garcia^{2

4}, Timothée Bruel^{3

5}, Ayrin Kök^{6

7}, Helene Strick-Marchand^{1

2}, Gregory Jouvion⁸, Nicolas Serafini^{1

2}, Ai Ing Lim^{1

2}, Mathilde Dusseaux^{1

2}, Thierry Hieu^{6

7}, Franck Bourgade⁹, Antoine Toubert^{10

11}, Daniela Finke^{12

13}, Olivier Schwartz^{3

5}, Philippe Bousso^{2

3

4}, Hugo Mouquet^{3

6

7}, James P Di Santo^{14

15}

Affiliations

¹ Innate Immunity Unit, Institut Pasteur, Paris, France.
² INSERM U1223, Paris, France.
³ Vaccine Research Institute, Creteil, France.
⁴ Dynamics of Immune Responses Unit, Institut Pasteur, Paris, France.
⁵ Virus and Immunity Unit, Institut Pasteur, Paris, France.
⁶ Humoral Response to Pathogens Laboratory, Institut Pasteur, Paris, France.
⁷ INSERM U1222, Paris, France.
⁸ Experimental Neuropathology Unit, Institut Pasteur, Paris, France.
⁹ Central Animal Facility, Institut Pasteur, Paris, France.
¹⁰ Laboratoire d'Immunologie et d'Histocompatibilité, Hôpital Saint-Louis, Paris, France.
¹¹ INSERM UMR1160, Institut Universitaire d'Hématologie, Paris, France.
¹² University of Basel Children's Hospital, Basel, Switzerland.
¹³ Developmental Immunology, University of Basel, Basel, Switzerland.
¹⁴ Innate Immunity Unit, Institut Pasteur, Paris, France. james.di-santo@pasteur.fr.
¹⁵ INSERM U1223, Paris, France. james.di-santo@pasteur.fr.

PMID: 30065364
DOI: 10.1038/s41592-018-0071-6

Abstract

Lymph nodes (LNs) facilitate the cellular interactions that orchestrate immune responses. Human immune system (HIS) mice are powerful tools for interrogation of human immunity but lack secondary lymphoid tissue (SLT) as a result of a deficiency in Il2rg-dependent lymphoid tissue inducer cells. To restore LN development, we induced expression of thymic-stromal-cell-derived lymphopoietin (TSLP) in a Balb/c Rag2^-/-Il2rg^-/-Sirpa^NOD (BRGS) HIS mouse model. The resulting BRGST HIS mice developed a full array of LNs with compartmentalized human B and T cells. Compared with BRGS HIS mice, BRGST HIS mice have a larger thymus, more mature B cells, and abundant IL-21-producing follicular helper T (T_FH) cells, and show enhanced antigen-specific responses. Using BRGST HIS mice, we demonstrated that LN T_FH cells are targets of acute HIV infection and represent a reservoir for latent HIV. In summary, BRGST HIS mice reflect the effects of SLT development on human immune responses and provide a model for visualization and interrogation of regulators of immunity.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
B-Lymphocytes / cytology
B-Lymphocytes / immunology
Cytokines / genetics
Cytokines / immunology
Female
HIV Infections / immunology
HIV-1
Humans
Immunoglobulin Class Switching
Interleukin Receptor Common gamma Subunit / deficiency
Interleukin Receptor Common gamma Subunit / genetics
Lymph Nodes / cytology
Lymph Nodes / growth & development*
Lymph Nodes / immunology*
Male
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Mice, Transgenic
Models, Immunological
T-Lymphocytes / cytology
T-Lymphocytes / immunology
Thymic Stromal Lymphopoietin
Virus Latency / immunology

Substances

Cytokines
Il2rg protein, mouse
Interleukin Receptor Common gamma Subunit
Thymic Stromal Lymphopoietin