T Cell Activation and Proliferation Characteristic for HIV-Nef Transgenic Mice Is Lymphopenia Induced

Abstract

The HIV-Nef protein has been implicated in generating high viral loads and T cell activation. Transgenic (tg) mice with constitutive T cell-specific Nef expression show a dramatic reduction in T cell number and highly increased T cell turnover. Previous studies in Nef tg mice attributed this T cell activation to a direct effect of Nef at the cellular level. Given the strongly reduced peripheral T cell numbers, we examined whether this enhanced T cell division might instead be lymphopenia induced. Adoptively transferred naive wild-type T cells into lymphopenic Nef tg mice showed high T cell turnover and obtained the same effector/memory phenotype as the autologous Nef tg T cells, supporting the idea that the microenvironment determines the phenotype of the T cells present. Moreover, in bone marrow chimeras from mixtures of wild-type and Nef tg bone marrow, with a full T cell compartment containing a small proportion of Nef tg T cells, Nef tg T cells kept a naive phenotype. These results demonstrate that T cell activation in the Nef tg mice is lymphopenia induced rather than due to a direct T cell-activating effect of Nef.

Adult AIDS-Like Disease in a Novel Inducible Human Immunodeficiency Virus Type 1 Nef Transgenic Mouse Model: CD4 + T-Cell Activation Is Nef Dependent and Can Occur in the Absence of Lymphophenia

“…These results contrast with the study by Koenen and coworkers, who reported no T-cell activation in similar mixed chimeric mice reconstituted with BM cells from wild-type and CD2/Nef Tg mice, expressing Nef in both CD4 and CD8 T cells (26). However, in these latter chimeras, the Nef Tg T cells constituted only 1 to 2% of the total peripheral LN T-cell compartment where activation was measured (26). Moreover, the authors did not document that these residual pLN Tg T cells expressed Nef.…”

“…Consistent with this latter scenario, we reported that in CD4C/HIV Nef Tg mice the extent of T-cell activation correlates with levels of Nef expression in CD4 ϩ T cells, thus suggesting a direct involvement of Nef in this activation (53). In contrast, Koenen and coworkers reported that T-cell activation in CD2/Nef Tg mice is induced indirectly by lymphophenia (26). In that study, chimeric mice, which were generated from a mixture of non-Tg and Nef Tg bone marrow (BM) cells, were not lymphopenic, and the donor-derived Nef-expressing Tg T cells did not show an activated phenotype.…”

“…Alternatively, Nef-expressing CD4 ϩ T cells may need to interact with other cells to be further activated; delayed trafficking or other factors may retard activation. Whatever the identity of the yet-unknown factor(s) contributing to activation of Nef-expressing CD4 ϩ T cells, it does not appear to be lymphopenia, as others have recently suggested (26).…”

“…In that study, chimeric mice, which were generated from a mixture of non-Tg and Nef Tg bone marrow (BM) cells, were not lymphopenic, and the donor-derived Nef-expressing Tg T cells did not show an activated phenotype. However, the donor Nef Tg T cells constituted only 1 to 2% of peripheral T cells of these chimeric mice (26). Clearly, alternative experimental approaches are needed to study this phenotype in a more physiological context.…”

Selective Expression of Human Immunodeficiency Virus Nef in Specific Immune Cell Populations of Transgenic Mice Is Associated with Distinct AIDS-Like Phenotypes

“…These results show that when Nef is expressed under the regulation of the mCD4, CD4E, or CD4F sequences, thymic and peripheral CD4 ϩ T cells are severely depleted to a degree comparable to that observed in CD4C/HIV Nef Tg mice, confirming previous studies in Tg mice expressing Nef with different T-cell-specific promoters (12,65,89 (58,65,89). FACS analysis showed that a larger proportion of Tg CD4 ϩ T cells expressed CD69 and CD25 cell surface markers and were CD44 high , CD45RB low , and CD62L low cells (Fig.…”