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Human delta like 1-expressing human mesenchymal stromal cells promote human T cell development and antigen-specific response in humanized NOD/SCID/IL-2R[Formula: see text]^null (NSG) mice.

ABSTRACT: Human delta-like 1 (hDlk1) is known to be able to regulate cell fate decisions during hematopoiesis. Mesenchymal stromal cells (MSCs) are known to exhibit potent immunomodulatory roles in a variety of diseases. Herein, we investigated in vivo functions of hDlk1^-hMSCs and hDlk1⁺hMSCs in T cell development and T cell response to viral infection in humanized NOD/SCID/IL-2Rγ^null (NSG) mice. Co-injection of hDlk1^-hMSC with hCD34⁺ cord blood (CB) cells into the liver of NSG mice markedly suppressed the development of human T cells. In contrast, co-injection of hDlk1⁺hMSC with hCD34⁺ CB cells into the liver of NSG dramatically promoted the development of human T cells. Human T cells developed in humanized NSG mice represent markedly diverse, functionally active, TCR V[Formula: see text] usages, and the restriction to human MHC molecules. Upon challenge with Epstein-Barr virus (EBV), EBV-specific hCD8⁺ T cells in humanized NSG mice were effectively mounted with phenotypically activated T cells presented as hCD45⁺hCD3⁺hCD8⁺hCD45RO⁺hHLA-DR⁺ T cells, suggesting that antigen-specific T cell response was induced in the humanized NSG mice. Taken together, our data suggest that the hDlk1-expressing MSCs can effectively promote the development of human T cells and immune response to exogenous antigen in humanized NSG mice. Thus, the humanized NSG model might have potential advantages for the development of therapeutics targeting infectious diseases in the future.

SUBMITTER: Kwon DH

PROVIDER: S-EPMC8134586 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Immunodeficient mice reconstituted with human hematopoietic stem cells enable the in vivo study of human hematopoiesis. In particular, NOD-scid-IL2R?(null) engrafted mice have been shown to have reasonable levels of T and B cell repopulation and can mount T-cell dependent responses; however, antigen-specific B-cell responses in this model are generally poor. We explored whether developmental defects in the immunoglobulin gene repertoire might be partly responsible for the low level of antibody responses in this model. Roche 454 sequencing was used to obtain over 685,000 reads from cDNA encoding immunoglobulin heavy (IGH) and light (IGK and IGL) genes isolated from immature, naïve, or total splenic B cells in engrafted NOD-scid-IL2R?(null) mice, and compared with over 940,000 reads from peripheral B cells of two healthy volunteers. We find that while naïve B-cell repertoires in humanized mice are chiefly indistinguishable from those in human blood B cells, and display highly correlated patterns of immunoglobulin gene segment use, the complementarity-determining region H3 (CDR-H3) repertoires are nevertheless extremely diverse and are specific for each individual. Despite this diversity, preferential D(H)-J(H) pairings repeatedly occur within the CDR-H3 interval that are strikingly similar across all repertoires examined, implying a genetic constraint imposed on repertoire generation. Moreover, CDR-H3 length, charged amino-acid content, and hydropathy are indistinguishable between humans and humanized mice, with no evidence of global autoimmune signatures. Importantly, however, a statistically greater usage of the inherently autoreactive IGHV4-34 and IGKV4-1 genes was observed in the newly formed immature B cells relative to naïve B or total splenic B cells in the humanized mice, a finding consistent with the deletion of autoreactive B cells in humans. Overall, our results provide evidence that key features of the primary repertoire are shaped by genetic factors intrinsic to human B cells and are principally unaltered by differences between mouse and human stromal microenvironments.

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Human delta like 1-expressing human mesenchymal stromal cells promote human T cell development and antigen-specific response in humanized NOD/SCID/IL-2R[Formula: see text]^null (NSG) mice.

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Dataset Information

Human delta like 1-expressing human mesenchymal stromal cells promote human T cell development and antigen-specific response in humanized NOD/SCID/IL-2R[Formula: see text]null (NSG) mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Human delta like 1-expressing human mesenchymal stromal cells promote human T cell development and antigen-specific response in humanized NOD/SCID/IL-2R[Formula: see text]^null (NSG) mice.