Garcia S, Dadaglio G, Gougeon ML; International Conference on AIDS.
Int Conf AIDS. 1996 Jul 7-12; 11: 39 (abstract no. We.A.3003).
Unite d'Oncologie Virale, Institut Pasteur, Paris, France. Fax: 33 1 45 68 89 09.
Objectives: The Hu-PBL SCID chimera are obtained by injection of SCID (Severe Combined Immunodeficiency) mice, characterized by a genetic defect in TCR and Ig gene recombination, with human PBL. This model has been used by different groups for in vivo studies of AIDS pathogenesis. However, although no GVHD was observed in these chimeras, their reconstitution could be promoted by a GVH reaction, which would biase studies performed with this model. In order to determine if such a reaction occurs in these chimeras, we have characterized the human Vbeta repertoire in the spleen of hu-PBL-SCID mice. Methods: SCID mice were injected ip with 20.10(6) human PBL. 2 months post-graft, splenic human cells were characterized, by cytofluorometry. The nature of the human subsets found in the spleen, the expression of activation markers and the TCR Vbeta repertoire were studied. TCR rearrangements and CDR3 size distribution of Vbeta transcripts were analyzed by RT-PCR on an automatic DNA sequencer using fluorescent Cbeta or Jbeta primers. Results and discussion: 2 months post-engraftment, a consistent number of human cells, mainly T cells, was detected in the spleen of Hu-PBL-SCID mice. Interestingly, these cells exhibited the phenotype of activated cells i.e. CD45RO+, CD38+, HLA-DR+. Moreover, for all chimeras, all tested human Vbeta subsets were submitted to under representation and/or expansion. Importantly, these quantitative modifications were associated with a severe restriction of the Vbeta repertoire, in the CDR3 size distribution pattern and in the number of Jbeta segments. These results show that human T cells engrafted in SCID mice are in vivo submitted to antigenic selection, probably related to murine host molecules. They strongly suggest the occurrence in vivo of a massive selection event promoting the reconstitution of the chimeras and probably related to a GVH process. In addition, human T cells were anergic in response to in vitro mitogenic or superantigenic activation and this anergy was associated with a decrease in the in vivo expression of CD28 molecule. In conclusion restrictions in the TCR repertoire associated with the altered function of engrafted T cells in Hu-PBL-SCID mice shown in the present study questions whether this model is appropriate for in vivo studies of HIV infections.
Publication Types:
Keywords:
- Acquired Immunodeficiency Syndrome
- Animals
- Antigens, CD
- Antigens, CD45
- Chimera
- Disease Models, Animal
- Graft vs Host Disease
- HIV Infections
- Hemolytic-Uremic Syndrome
- Humans
- In Vitro
- Mice
- Mice, SCID
- Models, Biological
- Receptors, Antigen, T-Cell
- Severe Combined Immunodeficiency
- Spleen
- T-Lymphocytes
- immunology
Other ID:
UI: 102225528
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