Thymic Selection Generates a Large T Cell Pool Recognizing a Self-Peptide in Humans

Zippelius, Alfred; Pittet, Mikaël J.; Batard, Pascal; Rufer, Nathalie; Smedt, Magda De; Guillaume, Philippe; Ellefsen, Kim; Valmori, Danila; Líénard, Danielle; Plum, Jean; MacDonald, H. Robson; Speiser, Daniel E.; Cerottini, Jean‐Charles; Romero, Pedro

doi:10.1084/jem.20011658

Cited by 131 publications

(141 citation statements)

References 50 publications

(91 reference statements)

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“…No expansion of ELA‐specific CD8 + T‐cells was observed priming in the absence of peptide (data not shown). Although it is established that ELA‐reactive CD8 + T‐cells in healthy donors can be defined as naïve T‐cells (characterized by a CD45RA + CCR7 + phenotype, a high TREC content and long telomeres) (Dutoit et al ., 2002; Zippelius et al ., 2002), we confirmed that ELA‐specific T‐cell priming in these donors was indeed occurring within the naïve (and not memory) CD8 + T‐cell compartment. For this purpose, we mixed purified naïve or memory CD8 + T‐cells separately with autologous CD8‐depleted PBMCs to initiate priming (Fig.…”

Section: Resultssupporting

confidence: 71%

Reduced naïve CD 8 ⁺ T ‐cell priming efficacy in elderly adults

et al. 2015

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SummaryAging is associated with impaired vaccine efficacy and increased susceptibility to infectious and malignant diseases. CD8+ T‐cells are key players in the immune response against pathogens and tumors. In aged mice, the dwindling naïve CD8+ T‐cell compartment is thought to compromise the induction of de novo immune responses, but no experimental evidence is yet available in humans. Here, we used an original in vitro assay based on an accelerated dendritic cell coculture system in unfractioned peripheral blood mononuclear cells to examine CD8+ T‐cell priming efficacy in human volunteers. Using this approach, we report that old individuals consistently mount quantitatively and qualitatively impaired de novo CD8+ T‐cell responses specific for a model antigen. Reduced CD8+ T‐cell priming capacity in vitro was further associated with poor primary immune responsiveness in vivo. This immune deficit likely arises as a consequence of intrinsic cellular defects and a reduction in the size of the naïve CD8+ T‐cell pool. Collectively, these findings provide new insights into the cellular immune insufficiencies that accompany human aging.

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Section: Resultssupporting

confidence: 71%

Reduced naïve CD 8 ⁺ T ‐cell priming efficacy in elderly adults

et al. 2015

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“…1 and 2. The frequency of MELOE-1-specific T cells is around ten times lower than the frequency of Melan-A-specific T cells (around 1 in 1 Â 10 4 in our study and up to 1 in 1 Â 10 3 in other studies) [13,14,26]. With the exception of the Melan-A antigen, few studies have established ex vivo frequencies of tumor antigenspecific T cells in peripheral blood, their low frequencies precluding their direct evaluation.…”

Section: Discussioncontrasting

confidence: 75%

“…This expression profile and the potential involvement of MELOE-1-specific CTL in modifying time to progression of TIL-treated patients strongly suggest that this antigen is a relevant target for the development of immunotherapy protocols in melanoma; however, a crucial point for the use of a tumor antigen in immunotherapy is the presence and frequency of a tumor reactive T-cell-specific repertoire in melanoma patients [11]. Again, with the exception of Melan-A-specific T cells, which are found at high frequencies (up to 1 in 1 Â 10 3 CD8 1 lymphocytes) in the blood of HLA-A2 1 healthy donors and melanoma patients [12][13][14], the frequencies of other antigenspecific T cells are much lower (in the range of 1 in 1 Â 10 7 for MAGE-A3-specific T cells in healthy donors [15]). Such a high frequency of Melan-A-specific T cells in healthy donors and melanoma patients has been associated with a dominant TCR Va usage by Melan-A-specific T cells [16,17].…”

Section: Introductionmentioning

confidence: 99%

Frequent occurrence of high affinity T cells against MELOE‐1 makes this antigen an attractive target for melanoma immunotherapy

et al. 2010

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We recently showed that the infusion of tumor infiltrating lymphocytes specific for the MELOE-1 antigen was associated with a prolonged relapse-free survival for HLA-A2 1 melanoma patients who received tumor infiltrating lymphocytes therapy. Here, we characterized the MELOE-1/A2-specific T-cell repertoire in healthy donors and melanoma patients to further support an immunotherapy targeting this epitope. Using tetramer enrichment followed by multicolor staining, we found that MELOE-1-specific T cells were present in the blood of healthy donors and patients at similar frequencies (around 1 in 1 Â 10 5 CD8 1 cells). These cells mainly displayed a naïve phenotype in 4/6 healthy donors and 3/6 patients, whereas high proportions of memory cells were observed in the remaining individuals of both groups. There was a recurrent usage of the Va12.1 chain for 17/18 MELOE-1-specific T-cell clones derived from healthy donors or patients, associated with diverse Vb chains and V(D)J junctional sequences. All clones derived from melanoma patients (9/9) were reactive against the MELOE-1 36-44 peptide and against HLA-A2 1 melanoma cell lines. This study documents the existence of a large TCR repertoire specific for the MELOE-1/A2 epitope and its capacity to give rise to antitumor CTL that supports the development of immunotherapies targeting this epitope.Key words: Immunotherapy . Melanoma . MELOE-1 . T-cell repertoire . TCR Introduction A key advance in tumor immunology in the past 15 years has been the elucidation of the antigenic basis of tumor cell recognition and destruction, which has opened the way to development of antigen-based immunotherapy in cancer patients. Tumor-associated antigens (TAA) have been grouped into categories according to their expression pattern in neoplastic and normal tissues. TAA can be roughly subdivided into two main classes: proteins expressed specifically by tumor cells, and proteins that are expressed by both tumor cells and by normal cells to a significant level. The first category includes cancergermline antigens, proteins expressed by unconventional gene expression and mutated antigens (see [1] for review). TAA belonging to the second category are the differentiation antigens, mainly expressed in the melanocytic lineage, and the antigens overexpressed by various tumor tissues. Although the immunogenicity of a number of TAA has been documented in clinical Ã These authors contributed equally to this work. We recently showed a correlation between the infusion of T cells reactive against an HLA-A2 epitope derived from another melanoma antigen, MELOE-1, and time to progression of patients treated with autologous tumor infiltrating lymphocytes (TIL) [10]. This antigen is encoded by the meloe gene, overexpressed in human melanoma cell lines, when compared to normal melanocytes, and dramatically underexpressed in other cancer cell lines (colon, renal, breast and lung carcinoma cell lines) and in a variety of normal tissues [10]. This expression profile and the potential involvement of MELOE-1-specific...

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“…To ensure that this technique could be applied to the enrichment of such a T cell population, we used Melan-A-specific T cells. Phenotypic [12], functional [13] and molecular techniques [14] have confirmed unequivocally that in normal individuals, these T cells are truly antigen naive. Following enrichment, Melan-Aspecific T cells could be found at a frequency of 83.78% of CD8 + T cells (Fig.…”

Section: Magnetic Selection Of Naive Populations Of Melan-a-specific mentioning

confidence: 86%

Ultra‐sensitive class I tetramer analysis reveals previously undetectable populations of antiviral CD8⁺ T cells

et al. 2004

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A major breakthrough in cellular immunology has been the development of HLA class I tetramers to analyze CD8 + T cell responses. However, in many situations, including persistent virus infection, specific T cell responses are rarely detected using this technology. This raises the question of whether such responses are 'deleted' (or 'exhausted') or present below the conventional detection limit for class I tetramer staining. In particular, persistent hepatitis C virus (HCV) infection is characterized by very weak or apparently absent specific CD8 + T cell responses, even though they are readily detectable in acute disease. Therefore, we assessed the use of anti-PE-labeled magnetic beads to enrich tetramer-positive HCVspecific T cells and identify previously undetectable populations. Using the enrichment technique, HCV-specific T cells could be detected in the majority of infected individuals, whereas these responses were not detected using conventional tetramer staining (8/15 vs. 1/15; p=0.01). Magnetic enrichment could reliably detect very rare HCV-specific responses at frequencies of G 0.0011% of CD8 + T cells (˚1/million PBMC), and phenotypic analysis of these rare populations was possible. Therefore, this direct ex vivo technique revealed the persistence of very low frequencies of virus-specific CD8 + T cells during chronic virus infection and is readily transferable to the study of other viral, self-or tumor-specific T cells.

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Thymic Selection Generates a Large T Cell Pool Recognizing a Self-Peptide in Humans

Cited by 131 publications

References 50 publications

Reduced naïve CD 8 ⁺ T ‐cell priming efficacy in elderly adults

Reduced naïve CD 8 ⁺ T ‐cell priming efficacy in elderly adults

Frequent occurrence of high affinity T cells against MELOE‐1 makes this antigen an attractive target for melanoma immunotherapy

Ultra‐sensitive class I tetramer analysis reveals previously undetectable populations of antiviral CD8⁺ T cells

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Thymic Selection Generates a Large T Cell Pool Recognizing a Self-Peptide in Humans

Cited by 131 publications

References 50 publications

Reduced naïve CD 8 + T ‐cell priming efficacy in elderly adults

Reduced naïve CD 8 + T ‐cell priming efficacy in elderly adults

Frequent occurrence of high affinity T cells against MELOE‐1 makes this antigen an attractive target for melanoma immunotherapy

Ultra‐sensitive class I tetramer analysis reveals previously undetectable populations of antiviral CD8+ T cells

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Reduced naïve CD 8 ⁺ T ‐cell priming efficacy in elderly adults

Reduced naïve CD 8 ⁺ T ‐cell priming efficacy in elderly adults

Ultra‐sensitive class I tetramer analysis reveals previously undetectable populations of antiviral CD8⁺ T cells