Low-affinity TCR engagement drives IL-2-dependent post-thymic maintenance of naive CD4+T cells in aged humans

Kornelis S. M. van der Geest, Wayel H. Abdulahad, Nato Teteloshvili, Sarah M. Tete, Jorieke H. Peters, Gerda Horst, Pedro G. Lorencetti, Nicolaas A. Bos, Annechien Lambeck, Caroline Roozendaal, Bart-Jan Kroesen, Hans J. P. M. Koenen, Irma Joosten, Elisabeth Brouwer, Annemieke M. H. Boots*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

13 Citaten (Scopus)
305 Downloads (Pure)

Samenvatting

Insight into the maintenance of naive T cells is essential to understand defective immune responses in the context of aging and other immune compromised states. In humans, naive CD4+ T cells, in contrast to CD8+ T cells, are remarkably well retained with aging. Here, we show that low-affinity TCR engagement is the main driving force behind the emergence and accumulation of naive-like CD4+ T cells with enhanced sensitivity to IL-2 in aged humans. In vitro, we show that these CD45RA(+)CD25(dim)CD4(+) T cells can develop from conventional naive CD25(-)CD4+ T cells upon CD3 cross-linking alone, in the absence of costimulation, rather than via stimulation by the homeostatic cytokines IL-2, IL-7, or IL-15. In vivo, TCR engagement likely occurs in secondary lymphoid organs as these cells were detected in lymph nodes and spleen where they showed signs of recent activation. CD45RA(+)CD25(dim)CD4+ T cells expressed a broad TCRV repertoire and could readily differentiate into functional T helper cells. Strikingly, no expansion of CD45RA(+)CD25(dim)CD8+ T cells was detected with aging, thereby implying that maintenance of naive CD4+ T cells is uniquely regulated. Our data provide novel insight into the homeostasis of naive T cells and may guide the development of therapies to preserve or restore immunity in the elderly.

Originele taal-2English
Pagina's (van-tot)744-753
Aantal pagina's10
TijdschriftAging Cell
Volume14
Nummer van het tijdschrift5
DOI's
StatusPublished - okt-2015

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