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Review
. 2023 Oct 5;11(10):2702.
doi: 10.3390/biomedicines11102702.

Legend or Truth: Mature CD4+CD8+ Double-Positive T Cells in the Periphery in Health and Disease

Magdalena Hagen  1 , Luca Pangrazzi  1 , Lourdes Rocamora-Reverte  1 , Birgit Weinberger  1
Affiliations
Review

Legend or Truth: Mature CD4+CD8+ Double-Positive T Cells in the Periphery in Health and Disease

Magdalena Hagen et al. Biomedicines. .

Abstract

The expression of CD4 and CD8 co-receptors defines two distinct T cell populations with specialized functions. While CD4+ T cells support and modulate immune responses through different T-helper (Th) and regulatory subtypes, CD8+ T cells eliminate cells that might threaten the organism, for example, virus-infected or tumor cells. However, a paradoxical population of CD4+CD8+ double-positive (DP) T cells challenging this paradigm has been found in the peripheral blood. This subset has been observed in healthy as well as pathological conditions, suggesting unique and well-defined functions. Furthermore, DP T cells express activation markers and exhibit memory-like features, displaying an effector memory (EM) and central memory (CM) phenotype. A subset expressing high CD4 (CD4bright+) and intermediate CD8 (CD8dim+) levels and a population of CD8bright+CD4dim+ T cells have been identified within DP T cells, suggesting that this small subpopulation may be heterogeneous. This review summarizes the current literature on DP T cells in humans in health and diseases. In addition, we point out that strategies to better characterize this minor T cell subset's role in regulating immune responses are necessary.

Keywords: CD4+CD8+ T cells; T cell development; T cell differentiation; adaptive immunity; aging; viral infections.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
T cell development and potential origin of mature CD4dim+CD8bright+ and CD4bright+CD8dim+ double-positive (DP) T cells. T cell progenitors (light blue) originating from the bone marrow enter the thymus (orange) as double-negative (DN) T cells, which lack the expression of both CD4 and CD8 co-receptors, to undergo positive and negative selections [2,3,38]. Immature DN T cells (light green) go through four stages of differentiation (DN1 to DN4) in which rearrangement of the T cell receptor (TCR) β-chain and the expression of a preTCR expression occur [3]. DN4 T cells undergo rearrangement of the α-chain of the TCR, leading to the transition to immature DP T cells, which express a rearranged TCR and both CD4 (red) and CD8 (turquoise) co-receptors [3]. DP T cells that recognize antigens presented via MHC class II receptors differentiate into mature CD4+ single-positive (SP) T cells (dark green), while recognition of antigens presented by MHC class I molecules results in mature CD8+ SP T cells, which leave the thymus into the periphery [25]. Despite the paradigm that peripheral T cells exclusively express either CD4 or CD8, mature CD4+CD8+ DP T cells were found outside the thymus [8]. These DP T cells can further be divided into two subsets, CD4dim+CD8bright+ and CD4bright+CD8dim+ T cells, respectively [16]. On the one hand, it was suggested that the activation of CD8+ SP T cells may lead to the surface expression of CD4, resulting in CD4dim+CD8bright+ T cells [30]. On the other hand, CD8 expression was suggested to be acquired by CD4+ SP T cells upon terminal differentiation, leading to a CD4bright+CD8dim+ T cell population [32,33]. Created with BioRender.com (accessed on 29.09.2023).
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This research received no external funding.