IL-2 receptor γ-chain molecule is critical for intestinal T-cell reconstitution in humanized mice

Abstract

Intestinal immune cells are important in host defense, yet the determinants for human lymphoid homeostasis in the intestines are poorly understood. In contrast, lymphoid homeostasis has been studied extensively in mice, where the requirement for a functional common γ-chain molecule has been established. We hypothesized that humanized mice could offer insights into human intestinal lymphoid homeostasis if generated in a strain with an intact mouse common γ-chain molecule. To address this hypothesis, we used three mouse strains (non-obese diabetic (NOD)/severe-combined immunodeficient (SCID) (N/S); NOD/SCID γ-chain−/− (NSG); and Rag2−/− γ-chain−/− (DKO)) and two humanization techniques (bone marrow liver thymus (BLT) and human CD34+ cell bone marrow transplant of newborn mice (hu)) to generate four common types of humanized mice: N/S-BLT, NSG-BLT, NSG-hu, and DKO-hu mice. The highest levels of intestinal human T cells throughout the small and large intestines were observed in N/S-BLT mice, which have an intact common γ-chain molecule. Furthermore, the small intestine lamina propria T-cell populations of N/S-BLT mice exhibit a human intestine-specific surface phenotype. Thus, the extensive intestinal immune reconstitution of N/S-BLT mice was both quantitatively and qualitatively better when compared with the other models tested such that N/S-BLT mice are well suited for the analysis of human intestinal lymphocyte trafficking and human-specific diseases affecting the intestines.

Human immune system development and survival of non-obese diabetic (NOD)-scid IL2rγnull (NSG) mice engrafted with human thymus and autologous haematopoietic stem cells

“…The persistence and functionality of human T cells was improved significantly by the use of NOD-scid mice as recipients of human thymic and liver tissues [22,23]. However, engraftment of fetal thymic and liver tissues into NSG mice enhances human cell chimerism significantly, including reconstitution of a mucosal immune system, compared to other mouse strains [17,65]. Continued improvement of the NSG mouse by the transgenic expression of human-specific cytokines and growth factors and expression of HLA that will allow matching with the donor tissues will further augment the development of human immune systems in BLT mice [3,66].…”

The use of BLT humanized mice to investigate the immune reconstitution of the gastrointestinal tract

“…A recent study by Denton et al investigated the differences and similarities in gut reconstitution between all of these humanized mouse models (Denton et al, 2012). This study presents a detailed head-to-head comparison between humanized DKO, NSG, NOD/SCID BLT and NSG BLT mice.…”

“…The authors noted that regardless of the mouse strain or the humanization protocol (i.e. transplantation alone or transplantation of thy/liv implanted animals) all mice were reconstituted as evidenced by the presence of human T cells in peripheral blood (Denton et al, 2012). …”

In vivo platforms for analysis of HIV persistence and eradication

“…Bone marrow engraftment also results in the production of virtually all other human hematopoietic cell types, including those directly relevant to HIV research such as monocytes, macrophages, and DCs. Human cells in BLT mice are systemically distributed throughout all organs analyzed, including bone marrow, lymph nodes, spleen, thymus, liver, lung, female and male reproductive tracts, and the upper and lower digestive tracts (53,61,(101)(102)(103). The wide distribution of human HIV target cells in mucosal sites renders BLT mice susceptible to rectal, vaginal, and oral HIV infection (55, 61-63, 65, 103, 104).…”