Preferential usage of Vα4 and Vβ10 T cell receptor genes by lymphocytic choriomeningitis virus glycoprotein‐specific H‐2Db‐restricted cytotoxic T cells

118

Immunoproteasome subunits low-molecular mass polypeptide (LMP)2 and LMP7 affect Ag presentation by MHC class I molecules. In the present study, we investigated the function of the third immunosubunit LMP10/multicatalytic endopeptidase complex-like (MECL)-1 (β2i) in MECL-1 gene-targeted mice. The number of CD8+ splenocytes in MECL-1−/− mice was 20% lower than in wild-type mice. Infection with lymphocytic choriomeningitis virus (LCMV) elicited a markedly reduced cytotoxic T cell (CTL) response to the LCMV epitopes GP276–286/Db and NP205–212/Kb in MECL-1−/− mice. The weak CTL response to GP276–286/Db was not due to an impaired generation of this epitope but was attributed to a decreased precursor frequency of GP276–286/Db-specific T cells. The expansion of TCR-Vβ10+ T cells, which contain GP276–286/Db-specific cells, was reduced in LCMV-infected MECL-1−/− mice. Taken together, our data reveal an in vivo function of MECL-1 in codetermining the T cell repertoire for an antiviral CTL response.

Section: The Generation Of V ␤ 10b-specific Ctls Is Impaired In Lcmv-mentioning

confidence: 90%

An Altered T Cell Repertoire in MECL-1-Deficient Mice

Basler

Moebius

Elenich

et al. 2006

118

“…The presence of public clonotypes and the global restriction of repertoire cannot be only attributed to the successive and repetitive stimulations of immune cells upon chronic infection, as the above public clonotype appeared early during acute infection (41,42). Different studies have also suggested that the structural constraints/mechanisms of the TCR-pMHC interaction (12,13,43,44) and the endogenous selection of T cells (45) might play an important role in the regulation of the level of TCR diversity.…”

Section: Discussionmentioning

confidence: 99%

Large TCR Diversity of Virus-Specific CD8 T Cells Provides the Mechanistic Basis for Massive TCR Renewal after Antigen Exposure

Miconnet

Marrau

Farina

et al. 2011

Ex vivo analysis of virus-specific CD8 T cell populations by anchored PCR has shown that the CD8 TCR repertoire was less oligoclonal (seven to nine clonotypes per individual epitope) than previously thought. In the current study, TCR diversity was investigated by assessing both the overall TCR β-chain variable regions usage as well as the CDR3 regions in ex vivo-isolated CMV- and EBV-specific CD8 T cells from 27 healthy donors. The average number of clonotypes specific to most single viral epitopes comprised between 14 and 77. Changes in the CD8 TCR repertoire were also longitudinally assessed under conditions of HIV-1 chronic infection (i.e., in patients with suppressed virus replication and after treatment interruption and Ag re-exposure). The results showed that a large renewal (≤80%) of the TRB repertoire occurred after Ag re-exposure and was eventually associated with an increased T cell recognition functional avidity. These results demonstrate that the global CD8 TCR repertoire is much more diverse (≤9-fold) than previously estimated and provide the mechanistic basis for supporting massive repertoire renewal during chronic virus infection and Ag re-exposure.

“…A factor that was shown to be a determinant of immunodominance at least in influenza infection is the availability of specific CTLs in the repertoire of peripheral T cell specificities (3,25). T cell lines specific for gp276 were strongly biased for the usage of V␣4 and V␤10 variable segements for their TCRs (38), but it has not been investigated whether this bias imposes a limit on the availability of gp276-specific T cells in the repertoire.…”

Section: Discussionmentioning

confidence: 99%

“…It has been shown that T cell lines specific for gp276 were using exclusively the V␤10 variable segment for their TCRs (38). Naive LMP2…”

Section: The Generation Of V␤10b-specific Ctls Is Impaired In Lcmv-inmentioning

confidence: 99%

Immunoproteasomes Down-Regulate Presentation of a Subdominant T Cell Epitope from Lymphocytic Choriomeningitis Virus

Basler¹,

Youhnovski²,

Broek

et al. 2004

105

The cytotoxic T cell response to pathogens is usually directed against a few immunodominant epitopes, while other potential epitopes are either subdominant or not used at all. In C57BL/6 mice, the acute cytotoxic T cell response against lymphocytic choriomeningitis virus is directed against immunodominant epitopes derived from the glycoprotein (gp33–41) and the nucleoprotein (NP396–404), while the gp276–286 epitope remains subdominant. Despite extensive investigations, the reason for this hierarchy between epitopes is not clear. In this study, we show that the treatment of cells with IFN-γ enhanced the presentation of gp33–41, whereas presentation of the gp276–286 epitope from the same glycoprotein was markedly reduced. Because proteasomes are crucially involved in epitope generation and because IFN-γ treatment in vitro and lymphocytic choriomeningitis virus infection in vivo lead to a gradual replacement of constitutive proteasomes by immunoproteasomes, we investigated the role of proteasome composition on epitope hierarchy. Overexpression of the active site subunits of immunoproteasomes LMP2, LMP7, and MECL-1 as well as overexpression of LMP2 alone suppressed the presentation of the gp276–286 epitope. The ability to generate gp276–286-specific CTLs was enhanced in LMP2- and LMP7-deficient mice, and macrophages from these mice showed an elevated presentation of this epitope. In vitro digests demonstrated that fragmentation by immunoproteasomes, but not constitutive proteasomes led to a preferential destruction of the gp276 epitope. Taken together, we show that LMP2 and LMP7 can at least in part determine subdominance and shape the epitope hierarchy of CTL responses in vivo.