Multidimensional Analysis Integrating Human T-Cell Signatures in Lymphatic Tissues with Sex of Humanized Mice for Prediction of Responses after Dendritic Cell Immunization

Frontiers in Immunology

Constantin von Kaisenberg¹  Valery Volk²  Andreas Schneider²  Bala Sai Sundarasetty²  Laura Gerasch²  Renata Stripecke²  Sebastian J. Theobald²  Candida Deves Roth²  Michael Meyer-Hermann³  Haralampos Hatzikirou³  Philippe A. Robert³  Andreas I. Reppas³  Constanca Figueiredo⁴  Loukia M. Spineli⁵  Ulrike Koehl⁶  Stephan Klöss⁶ 

[1] Clinic of Gynecology and Obstetrics, Hannover Medical School, Hannover, Germany;Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany;Department of Systems Immunology, Braunschweig Integrated Centre of Systems Biology, Helmholtz Centre for Infection Research, Braunschweig, Germany;Department of Transfusion Medicine, Hannover Medical School, Hannover, Germany;Institute of Biostatistics, Hannover Medical School, Hannover, Germany;Institute of Cellular Therapeutics and GMP Core Facility IFB-Tx, Hannover Medical School, Hannover, Germany;

关键词: hematopoietic stem cell transplantation;    cord blood;    dendritic cell;    T cell maturation;    lymphatic;    humanized mice;   

DOI  :  10.3389/fimmu.2017.01709

来源: DOAJ

【 摘 要 】

Mice transplanted with human cord blood-derived hematopoietic stem cells (HSCs) became a powerful experimental tool for studying the heterogeneity of human immune reconstitution and immune responses in vivo. Yet, analyses of human T cell maturation in humanized models have been hampered by an overall low immune reactivity and lack of methods to define predictive markers of responsiveness. Long-lived human lentiviral induced dendritic cells expressing the cytomegalovirus pp65 protein (iDCpp65) promoted the development of pp65-specific human CD8+ T cell responses in NOD.Cg-Rag1tm1Mom-Il2rγtm1Wj humanized mice through the presentation of immune-dominant antigenic epitopes (signal 1), expression of co-stimulatory molecules (signal 2), and inflammatory cytokines (signal 3). We exploited this validated system to evaluate the effects of mouse sex in the dynamics of T cell homing and maturation status in thymus, blood, bone marrow, spleen, and lymph nodes. Statistical analyses of cell relative frequencies and absolute numbers demonstrated higher CD8+ memory T cell reactivity in spleen and lymph nodes of immunized female mice. In order to understand to which extent the multidimensional relation between organ-specific markers predicted the immunization status, the immunophenotypic profiles of individual mice were used to train an artificial neural network designed to discriminate immunized and non-immunized mice. The highest accuracy of immune reactivity prediction could be obtained from lymph node markers of female mice (77.3%). Principal component analyses further identified clusters of markers best suited to describe the heterogeneity of immunization responses in vivo. A correlation analysis of these markers reflected a tissue-specific impact of immunization. This allowed for an organ-resolved characterization of the immunization status of individual mice based on the identified set of markers. This new modality of multidimensional analyses can be used as a framework for defining minimal but predictive signatures of human immune responses in mice and suggests critical markers to characterize responses to immunization after HSC transplantation.

【 授权许可】

Unknown