Quantification of lymph node transit times reveals differences in antigen surveillance strategies of naïve CD4
            <sup>+</sup>
            and CD8
            <sup>+</sup>
            T cells

Mandl, Judith N.; Liou, Rachel; Klauschen, Frederick; Vrisekoop, Nienke; Monteiro, João P.; Yates, Andrew J.; Huang, Alex Y.; Germain, Ronald N.

doi:10.1073/pnas.1211717109

Cited by 139 publications

(150 citation statements)

References 40 publications

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“…Although the molecular details are not yet known, it is tempting to speculate that thymic assortment and peripheral response mode share a molecular basis. The theme of higher dependency on MHCderived signals extends to naive CD4 + T cells that traverse LNs in an MHC-dependent manner and adjust CD5 levels to TCR affinity, whereas CD8 + T cells do not (49,70). In addition, the CD4 + T memory cells recirculate more freely through tissues, while their CD8 + counterparts are confined in an Ag-independent way at the infection site (71,72).…”

Section: Discussionmentioning

confidence: 99%

Differential Kinetics of Antigen Dependency of CD4+ and CD8+ T Cells

Rabenstein

Ellwart

et al. 2014

The Journal of Immunology

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Ag recognition via the TCR is necessary for the expansion of specific T cells that then contribute to adaptive immunity as effector and memory cells. Because CD4+ and CD8+ T cells differ in terms of their priming APCs and MHC ligands we compared their requirements of Ag persistence during their expansion phase side by side. Proliferation and effector differentiation of TCR transgenic and polyclonal mouse T cells were thus analyzed after transient and continuous TCR signals. Following equally strong stimulation, CD4+ T cell proliferation depended on prolonged Ag presence, whereas CD8+ T cells were able to divide and differentiate into effector cells despite discontinued Ag presentation. CD4+ T cell proliferation was neither affected by Th lineage or memory differentiation nor blocked by coinhibitory signals or missing inflammatory stimuli. Continued CD8+ T cell proliferation was truly independent of self-peptide/MHC-derived signals. The subset divergence was also illustrated by surprisingly broad transcriptional differences supporting a stronger propensity of CD8+ T cells to programmed expansion. These T cell data indicate an intrinsic difference between CD4+ and CD8+ T cells regarding the processing of TCR signals for proliferation. We also found that the presentation of a MHC class II–restricted peptide is more efficiently prolonged by dendritic cell activation in vivo than a class I bound one. In summary, our data demonstrate that CD4+ T cells require continuous stimulation for clonal expansion, whereas CD8+ T cells can divide following a much shorter TCR signal.

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Section: Discussionmentioning

confidence: 99%

Differential Kinetics of Antigen Dependency of CD4+ and CD8+ T Cells

Rabenstein

Ellwart

et al. 2014

The Journal of Immunology

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“…Mandl et al 36 have recently shown that interactions with MHC class II molecules retained CD4 T N cells in LNs. By using the same protocol (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…CD5 expression on CD4 T N cells has been shown to be adjusted to reflect TCR contact with self [34][35][36][37] . In fact, the more a CD4 T N cell interacts with self, the more this cell expresses CD5.…”

Section: Resultsmentioning

confidence: 99%

Highly self-reactive naive CD4 T cells are prone to differentiate into regulatory T cells

et al. 2013

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Upon activation, naive CD4 T cells differentiate into a variety of T-helper-cell subsets characterized by different cytokine production and functions. Currently, lineage commitment is considered to depend mostly on the environmental context to which naive CD4 T cells are exposed. Here we challenge this model based on the supposed homogeneity of the naive CD4 T-cell compartment. We show that peripheral naive CD4 T cells can be subdivided into two subsets according to Ly-6C expression. Furthermore, the two newly defined subsets (Ly-6C À and Ly-6C þ naive CD4 T cells) are not equal in their intrinsic ability to commit into the induced regulatory T-cell lineage. Finally, phenotypic analysis, imaging and adoptive transfer experiments reveal that Ly-6C expression is modulated by self-recognition, allowing the dichotomization of the naive CD4 T-cell compartment into two cell subsets with distinct self-reactivity. Altogether, our results show that naive CD4 T cells with the highest avidity for self are prone to differentiate into regulatory T cells.

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“…This, however, does not rule out the possibility that CD5 surface levels may be dynamically tuned in response to self-pMHC availability [23]. The loss of sub-threshold TCR signalling upon the abrogation of the interaction of T cells with MHC leads to a decrease in CD5 levels [21,24]. Therefore, CD5 levels may be a function of the net signal obtained from self-ligands which will depend on TCR avidity as well as the presence of competing T cells "consuming" the same available ligand.…”

Section: Increased Lip Of Cd4 + T Cells With Greater Self-pmhc Reactimentioning

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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Quantification of lymph node transit times reveals differences in antigen surveillance strategies of naïve CD4 ⁺ and CD8 ⁺ T cells

Cited by 139 publications

References 40 publications

Differential Kinetics of Antigen Dependency of CD4+ and CD8+ T Cells

Differential Kinetics of Antigen Dependency of CD4+ and CD8+ T Cells

Highly self-reactive naive CD4 T cells are prone to differentiate into regulatory T cells

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

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Quantification of lymph node transit times reveals differences in antigen surveillance strategies of naïve CD4 + and CD8 + T cells

Cited by 139 publications

References 40 publications

Differential Kinetics of Antigen Dependency of CD4+ and CD8+ T Cells

Differential Kinetics of Antigen Dependency of CD4+ and CD8+ T Cells

Highly self-reactive naive CD4 T cells are prone to differentiate into regulatory T cells

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

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Quantification of lymph node transit times reveals differences in antigen surveillance strategies of naïve CD4 ⁺ and CD8 ⁺ T cells