In vivo antagonism of a T cell response by an endogenously expressed ligand

To counter highly mutable pathogens like HIV-1, a number of vaccines are being developed to deliver multiple mutant forms of viral Ags to provoke multivalent antiviral CTLs. However, it is uncertain whether such multiple mutant epitope vaccines will generate the diverse CTL responses desired or will instead create immune interference. To characterize the role of immune interference by mutant epitopes in this process, we have tested a “worst case” scenario in which the immunodominant epitope of OVA (SIINFEKL) and its in vitro TCR antagonist (SIINFEDL) have been used to genetically immunize C57BL/6 mice. We demonstrate here that sequential delivery of these mutant epitopes provokes original antigenic sin in CD8 T cells as demonstrated by attenuation of CTLs, intracellular IFN-γ production, and MHC I peptide-tetramer staining. By contrast, simultaneous exposure of the immune system to this agonist/antagonist pair not only fails to generate T cell antagonism in vivo, but also avoids original antigenic sin. These observations suggest that simultaneous immunization with vaccines containing mutant epitopes, even T cell antagonists, can indeed generate a diverse array of T cell responses and that at least some immune interference can be avoided by delivering mutant Ags to the immune system simultaneously.

Section: Figuresupporting

confidence: 72%

The Role of T Cell Antagonism and Original Antigenic Sin in Genetic Immunization

Singh

Rodgers

Barry

2002

“…In agreement with this hypothesis, several epitope analogs that antagonize mature T cell responses were able to induce positive selection in fetal thymus organ cultures (FTOC) 3 (9,10). In contrast, others have shown that the presence of an antagonist peptide not only failed to promote positive selection but also impaired functional response of mature T cells to Ags (11,12). However, very few natural selfpeptides that promote positive selection have been identified to date and none is an antagonist (13)(14)(15)(16)(17).…”

mentioning

confidence: 61%

“…The presence of endogenous antagonists seems to inhibit mature T cell responses in the CD4 ϩ lineage (11,12,31). We have shown that Ube1x 509 -517 selects functional H-Y specific thymocytes (Fig.…”

Section: Discussionmentioning

confidence: 99%

Cutting Edge: Positive Selection Induced by a Self-Peptide with TCR Antagonist Activity

Santori

Brown

et al. 2001

Antagonist-like engagement of the TCR has been proposed to induce T cell selection in the thymus. However, no natural TCR ligand with TCR antagonist activity is presently known. Using a combination of bioinformatics and functional testing we identified the first self-peptide that can both deliver antagonist-like signals and promote T cell selection in the thymus. The peptide is presented by appropriate MHC class I molecules in vivo. Thus, endogenous antagonist peptides exist and may be involved in TCR repertoire selection.

“…There are similarities in the characteristics of cytokine gene expression between the SCID T cells described here and T cells that were anergized either with altered peptide ligands (50) or by insufficient stimulation through the TCR. In both SCID T cells and anergic T cells the proliferative response to stimuli is reduced, and IL-2 transcription is strongly compromised.…”

Section: Discussionmentioning

confidence: 92%

The Duration of Nuclear Residence of NFAT Determines the Pattern of Cytokine Expression in Human SCID T Cells

Feske

Draeger

Peter

et al. 2000

124

The expression of cytokine genes and other inducible genes is crucially dependent on the pattern and duration of signal transduction events that activate transcription factor binding to DNA. Two infant patients with SCID and a severe defect in T cell activation displayed an aberrant regulation of the transcription factor NFAT. Whereas the expression levels of the NFAT family members NFAT1, -2, and -4 were normal in the patients’ T cells, dephosphorylation and nuclear translocation of these NFAT proteins occurred very transiently and incompletely upon stimulation. Only after inhibition of nuclear export with leptomycin B were we able to demonstrate a modest degree of nuclear translocation in the patients’ T cells. This transient activation of NFAT was not sufficient to induce the expression of several cytokines, including IL-2, IL-3, IL-4, and IFN-γ, whereas mRNA levels for macrophage inflammatory protein-1α, GM-CSF, and IL-13 were only moderately reduced. By limiting the time of NFAT activation in normal control cells using the calcineurin inhibitor cyclosporin A, we were able to mimic the cytokine expression pattern in SCID T cells, suggesting that the expression of different cytokine genes is differentially regulated by the duration of NFAT residence in the nucleus.