The CD8 Population in CD4-deficient Mice Is Heavily Contaminated with MHC Class II–restricted T Cells

The specificity for self-MHC that is necessary for T cell function is a consequence of intrathymic selection during which T cell antigen receptors (TCRs) expressed by immature thymocytes are tested for their affinity for self-peptide:self-MHC. The germ-line-encoded segments of the TCR, however, are believed to have an innate specificity for structural features of MHC molecules. We directly tested this hypothesis by generating a transgenic mouse system in which the protein HLA-DM is expressed at the surface of thymic cortical epithelial cells in the absence of classical MHC molecules. The specialized intracellular function of HLA-DM has removed this MHC class II-like protein from the evolutionary forces that have been hypothesized to shape TCR-MHC interactions. Our study shows that a structural mimic of MHC class II is not sufficient to appropriately interact with the TCRs expressed by developing thymocytes. This result emphasizes the unique complementarity of TCR-MHC interactions that are maintained by the evolutionary pressures dictated by positive selection.T cell receptor ͉ thymocytes ͉ mice ͉ T lymphocytes ͉ thymus D evelopment of thymocytes is a multistep process that shapes the repertoire of mature T cells. Ideally, the mature T cell antigen receptor (TCR) repertoire is depleted of specificities that are overtly self-reactive, but is also diversified enough to mount effective immune responses (1, 2). Selection is based on the interactions of the TCRs expressed by immature CD4 ϩ CD8 ϩ , double-positive (DP) thymocytes with selfpeptide:self-MHC expressed on the surface of thymic stromal cells. Poorly defined criteria determine whether this receptorligand interaction is of sufficient avidity to drive development of DP thymocytes to mature single-positive, MHC class I-or MHC class II-restricted T cells.Unresolved issues regarding the positive selection of T cells include the extent that specific interactions of the TCR with MHC-bound self-peptides rather than interactions with MHC itself shape the mature CD4 ϩ T cell repertoire. This question has been addressed by a number of systems that have not produced concordant results (3-7). Such contradictory data have led to speculation that different TCRs may have different requirements for recognition of MHC-bound self-peptide. The inherent MHC reactivity of the preselection TCR repertoire is a second issue that has not been definitively answered. In other words, it is not clear whether the germ line-encoded regions of the TCR are predisposed toward interactions with MHC, or, alternatively, whether the ability of TCRs expressed by mature T cells to interact with MHC is fully a consequence of positive selection.Mutagenesis studies have suggested that the TCR has a conserved orientation of interaction with MHC molecules, and, therefore, conserved interactions between MHC molecules and TCRs seemed likely. Crystallographic studies of TCRs bound to MHC, however, have not fully confirmed this prediction (7). In retrospect, perhaps this finding is not surprising, consideri...

Section: Resultsmentioning

confidence: 99%

Coevolution of TCR-MHC interactions: Conserved MHC tertiary structure is not sufficient for interactions with the TCR

Kim

Guo

Sant’Angelo

2005

“…We have not examined the effect(s) of the CD4 molecule on the generation of memory CD8 cells, which is the subject of future investigation. There is recent evidence from Tyznik et al (43) and Pearce et al (44) that a subset of CD8 ϩ T cells in CD4 Ϫ/Ϫ mice react with MHC class II-restricted epitopes. Our studies show a similar quantitative defect in CD8 cells from CD4 Ϫ/Ϫ mice as that seen from these studies.…”

Section: Discussionmentioning

confidence: 99%

The CD4 molecule on CD8⁺T lymphocytes directly enhances the immune response to viral and cellular antigens

Kitchen

Whitmire

Jones

et al. 2005

CD8 ؉ T lymphocytes play a major role in cellular-mediated immune responses to foreign antigen. We have previously demonstrated that costimulation of purified human CD8 ؉ T cells induces de novo expression of the CD4 molecule and that ligation of CD4 on this cell type modulates CD8 ؉ T cell activity in vitro. Herein, we investigate how the CD4 molecule expressed on murine CD8 ؉ T cells contributes to CD8 ؉ cell responses in vivo by employing adoptive transfer of CD8 cells from CD4 knockout mice into severe combined immunodeficient (SCID) recipients. Transfer of these cells into syngeneic SCID mice resulted in a decreased immune response to infection by lymphocytic choriomeningitis virus. These decreased responses occurred even in the presence of CD4 ؉ T cells, indicating that this was truly a CD8-cell defect. Similarly, transfer of CD8 ؉ T cells incapable of expressing CD4 into allogeneic SCID mice resulted in a decreased response to alloantigens compared with that of normal CD8 ؉ T cells. Therefore, CD4 expression on CD8 T lymphocytes modulates cytotoxic T lymphocyte function and is critical in vivo for optimal cell-mediated immunity to viral and alloantigens.antiviral response ͉ CD8 ϩ T cells ͉ alloantigen response ͉ cytotoxic T lymphocytes T cell development in the thymus is characterized by the appearance and disappearance of cell-surface CD4 and CD8, which are classic markers of ontogeny. It was previously thought that after synchronous expression of CD4 and CD8, the developing thymocyte becomes CD4 or CD8 single positive, permanently turning off expression of one of these molecules. These single-positive cells are then exported to the periphery to perform their respective functions: CD4 ϩ cells serving primarily as T helper (Th) cells, and CD8 ϩ cells serving primarily as cytotoxic T lymphocytes (CTLs). Our current investigation focuses on the CD8 ϩ T cell population. CD8 ϩ T cells become activated to perform their function when they encounter a specific antigen presented in the context of MHC class I and are costimulated by one of many molecules present on antigen-presenting cells (APCs) (1). A well described series of events is triggered after activation of CD8 ϩ T cells, primarily resulting in CTLs that kill antigen-expressing target cells.In contrast to the notion that commitment to the CD4 or CD8 lineage is complete or permanent after thymopoiesis, extrathymic CD8 ϩ CD4 ϩ cells have been identified in many organisms, including humans, monkeys, mice, rats, swine, and chickens (reviewed in ref.2). Various disease conditions appear to affect the levels of CD8 ϩ CD4 ϩ T cells. In humans, infection with HIV, human T cell leukemia virus, Epstein-Barr virus, human herpesvirus 6, and increasing age have been linked with increased percentages of CD8 ϩ CD4 ϩ T cells in the peripheral blood (3-6). In mice, increases in the CD8 ϩ CD4 ϩ population have been observed after inoculation with reovirus (7), or recombinant adenovirus (8). In most cases, the rise in the percentage of CD8 ϩ CD4 ϩ cells appears to be a dir...

“…1C) (21). Moreover, after infection with various pathogens, CD4 Ϫ/Ϫ mice produce CD8 ϩ T cells that react specifically with strong pMHC-II agonists (50,51). Similarly, CD4 ϩ 2C T cells respond to a potent pMHC-I agonist (QL9-L d ) for the 2C TCR (5).…”

Section: Discussionmentioning

confidence: 99%

Stage-dependent reactivity of thymocytes to self-peptide–MHC complexes

Leng

Nguyen

et al. 2007