Competition for self-peptide-MHC complexes and cytokines between naïve and memory CD8
            <sup>+</sup>
            T cells expressing the same or different T cell receptors

Ge, Qing; Bai, Ailin; Jones, Brendan; Eisen, Herman N.; Chen, Jianzhu

doi:10.1073/pnas.0307339101

Cited by 64 publications

(68 citation statements)

References 45 publications

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“…naive T cells undergo LIP may be reliant on TCR affinity for peptide-MHC 1,[4][5][6][7] . Accordingly, we asked whether PTPN2 levels may correlate with the extent of LIP, so that fast proliferating cells with higher affinity TCRs may have elevated PTPN2.…”

Section: Resultsmentioning

confidence: 99%

PTPN2 attenuates T-cell lymphopenia-induced proliferation

2014

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When the peripheral T-cell pool is depleted, T cells undergo homoeostatic expansion. This expansion is reliant on the recognition of self-antigens and/or cytokines, in particular interleukin-7. The T cell-intrinsic mechanisms that prevent excessive homoeostatic T-cell responses and consequent overt autoreactivity remain poorly defined. Here we show that protein tyrosine phosphatase N2 (PTPN2) is elevated in naive T cells leaving the thymus to restrict homoeostatic T-cell proliferation and prevent excess responses to self-antigens in the periphery. PTPN2-deficient CD8 þ T cells undergo rapid lymphopenia-induced proliferation (LIP) when transferred into lymphopenic hosts and acquire the characteristics of antigenexperienced effector T cells. The enhanced LIP is attributed to elevated T-cell receptordependent, but not interleukin-7-dependent responses, results in a skewed T-cell receptor repertoire and the development of autoimmunity. Our results identify a major mechanism by which homoeostatic T-cell responses are tuned to prevent the development of autoimmune and inflammatory disorders.

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Section: Resultsmentioning

confidence: 99%

PTPN2 attenuates T-cell lymphopenia-induced proliferation

2014

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“…These donor T cells home, as do all T cells, to lymphoid organs (23,24), and there they carry out destructive graft-vs.-host reactions, compromising or eliminating these tissues wherein immune responses to exogenous antigens take place. In addition, mature donor T cells expand in response to minor antigens present at a high frequency at the time of transplantation (25,26), and thereby suppress the production of naive T cells by rapidly saturating the lymphocyte pool (27)(28)(29). A monotonous phenotype of effector memory cells defined by loss of CD62L expression and acquisition of CD44 predominated the peripheral T-cell pool in recipients of bulk T-cell-replete grafts.…”

Section: Hsc Grafts Enhance Lymphoid Reconstitution and De Novo Regenmentioning

confidence: 99%

Co-transplantation of pure blood stem cells with antigen-specific but not bulk T cells augments functional immunity

Müller

Shashidhar

Küpper

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Impaired immunity is a fundamental obstacle to successful allogeneic hematopoietic cell transplantation. Mature graft T cells are thought to provide protection from infections early after transplantation, but can cause life-threatening graft-vs.-host disease. Human CMV is a major pathogen after transplantation. We studied reactivity against the mouse homologue, murine CMV (MCMV), in lethally irradiated mice given allogeneic purified hematopoietic stem cells (HSCs) or HSCs supplemented with T cells or T-cell subsets. Unexpectedly, recipients of purified HSCs mounted superior antiviral responses compared with recipients of HSC plus unselected bulk T cells. Furthermore, supplementation of purified HSC grafts with CD8 + memory or MCMV-specific T cells resulted in enhanced antiviral reactivity. Posttransplantation lymphopenia promoted massive expansion of MCMV-specific T cells when no competing donor T cells were present. In recipients of pure HSCs, naive and memory T cells and innate lymphoid cell populations developed. In contrast, the lymphoid pool in recipients of bulk T cells was dominated by effector memory cells. These studies show that pure HSC transplantations allow superior protective immunity against a viral pathogen compared with unselected mature T cells. This reductionist transplant model reveals the impact of graft composition on regeneration of host, newly generated, and mature transferred T cells, and underscores the deleterious effects of bulk donor T cells. Our findings lead us to conclude that grafts composed of purified HSCs provide an optimal platform for in vivo expansion of selected antigen-specific cells while allowing the reconstitution of a naive T-cell pool.

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“…Interestingly, there is heterogeneity in the number of divisions distinct clonotypes undergo in T-cell deficient hosts [14][15][16]. It has previously been assumed that intrinsic differences dictate whether or not a TCR clonotype is capable of homeostatic expansion, with some T cells having a self-reactivity that is simply too low to obtain enough signal from MHC interactions to lead to division [2,3,17]. However, as the availability of different self-pMHC may vary widely, or because the amount of integrated signal required for division may be greater for T cells with low self reactivity, the extent of LIP could also be a function of the intensity of competition experienced by T-cell clonotypes that limits the signals received through the TCR.…”

mentioning

confidence: 99%

Weakly self‐reactive T‐cell clones can homeostatically expand when present at low numbers

et al. 2016

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T-cell division is central to maintaining a stable T-cell pool in adults. It also enables T-cell expansion in neonates, and after depletion by chemotherapy, bone marrow transplantation, or infection. The same signals required for T-cell survival in lymphoreplete settings, IL-7 and T-cell receptor (TCR) interactions with self-peptide MHC (pMHC), induce division when T-cell numbers are low. The strength of reactivity for self-pMHC has been shown to correlate with the capacity of T cells to undergo lymphopenia-induced proliferation (LIP),in that weakly self-reactive T cells are unable to divide, implying that T-cell reconstitution would significantly skew the TCR repertoire toward TCRs with greater self-reactivity and thus compromise T-cell diversity. Here, we show that while CD4 + T cells with low self-pMHC reactivity experience more intense competition, they are able to divide when present at low enough cell numbers. Thus, at physiological precursor frequencies CD4 + T cells with low self-pMHC reactivity are able to contribute to the reconstitution of the T-cell pool.Keywords: Lymphopenia-induced proliferation r Regulation of homeostasis r T-cell competition r T-cell diversity r T-cell repertoire Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionThe size of the naïve T-cell pool is tightly regulated. On average, naïve T cells are long-lived, but both in humans and mice there is continual turnover with cells dying and being replaced. Two sources of renewal contribute to naïve T-cell maintenance: de novo production in the thymus and proliferation within secondary Correspondence: Dr. Nienke Vrisekoop and Dr. Judith Mandl e-mail: n.vrisekoop@umcutrecht.nl; judith.mandl@mcgill.ca lymphoid organs. In adults, when thymic production diminishes, 90% of daily naïve T-cell production derives from proliferation [1]. Moreover, restoration of naïve T-cell numbers after acute T-cell depletion, whether caused by infection, chemotherapy, or bone marrow transplantation requires cell division. Both naïve T-cell division and cell survival are dependent on extrinsic cues provided by IL-7 and tonic trophic signals obtained via the T-cell receptor (TCR) through interaction with specific self-pMHC [2][3][4][5][6][7].It is well-established that T-cell division during antigen-specific responses is a function of the number of the antigen-specific T cells present, such that large numbers of T cells with the same TCR inhibits their expansion [8,9]. There is also evidence that T cells compete for the sub-threshold self-pMHC signals critical to T-cell maintenance. In lympho-replete mice, T cells have a longer average life span when there are less competitor cells present with the same TCR [10]. Furthermore, during lymphopenia-induced proliferation (LIP), T cells divide in the presence of T cells with a distinct TCR, but not when there are large numbers of T cells present with the same TCR [11][12][13]. This suggests that signals obtained from sub-threshold interactions...

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Competition for self-peptide-MHC complexes and cytokines between naïve and memory CD8 ⁺ T cells expressing the same or different T cell receptors

Cited by 64 publications

References 45 publications

PTPN2 attenuates T-cell lymphopenia-induced proliferation

PTPN2 attenuates T-cell lymphopenia-induced proliferation

Co-transplantation of pure blood stem cells with antigen-specific but not bulk T cells augments functional immunity

Weakly self‐reactive T‐cell clones can homeostatically expand when present at low numbers

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Competition for self-peptide-MHC complexes and cytokines between naïve and memory CD8 + T cells expressing the same or different T cell receptors

Cited by 64 publications

References 45 publications

PTPN2 attenuates T-cell lymphopenia-induced proliferation

PTPN2 attenuates T-cell lymphopenia-induced proliferation

Co-transplantation of pure blood stem cells with antigen-specific but not bulk T cells augments functional immunity

Weakly self‐reactive T‐cell clones can homeostatically expand when present at low numbers

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Competition for self-peptide-MHC complexes and cytokines between naïve and memory CD8 ⁺ T cells expressing the same or different T cell receptors