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

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.

miR-142 favors naïve B cell residence in peripheral lymph nodes.

B lymphocyte development proceeds through a well-ordered sequence of steps, leading to the formation of a sizeable mature B population recognizing a diversity of antigens. These latter cells are ultimately responsible for the production of antibodies upon immune challenges. The detection of threats to the organism is facilitated by the ability of naïve follicular B cells, the main subset of mature B cells in mice, to circulate between lymphoid tissues in search of their cognate antigens. miRNA-mediated fine-tuning of mRNA stability and translation participates in the optimal expression of genetic programs. This regulatory mechanism has been shown to contribute to B cell biology, although the role of individual miRNAs remains understudied. Here, we selectively inactivated the miR-142 locus in B cells. As a consequence, the mature B compartment was visibly perturbed, in agreement with work in miR-142 knockout mice. However, our strategy allowed us to identify roles for the miR-142 locus in B cell physiology obscured by the complexity of the immune phenotype in the null mutant mice. Thus, these miRNAs are necessary for the proper formation of the pre-B cell compartment during development. More remarkably, naïve follicular B cells demonstrated altered migratory properties upon conditional inactivation of the miR-142 locus. The latter mutant cells expressed reduced levels of the homing molecule CD62L. They also migrated more efficiently towards sphingosine-1-phosphate in vitro and displayed an increased abundance of the sphingosine-1-phosphate receptor 1, compatible with improved lymphocyte egress in vivo. In line with these observations, the ablation of the miR-142 locus in B cells caused a paucity of B cells in the lymph nodes. Mutant B cell accumulation in the latter tissues was also compromised upon transfer into a wild-type environment. These changes coincided with suboptimal levels of FOXO1, a positive regulator of CD62L transcription, in mutant B cells. Overall, our findings indicate contributions for the miR-142 locus in various aspects of the B cell life cycle. Notably, this locus appears to favor the establishment of the migratory behavior required for naïve follicular B cell patrolling activity.

Inflammation and the Alteration of B-Cell Physiology in Aging.

Aging results for the immune system in a departure from the optimal homeostatic state seen in young organisms. This divergence regrettably contributes to a higher frequency of compromised responses to infections and inefficient classical vaccination in aged populations. In B cells, the cornerstone of humoral immunity, the development and distribution of the various mature B cell subsets are impacted by aging in both humans and mice. In addition, aged mature B cells demonstrate limited capacity to mount efficient antibody responses. An expected culprit for the decline in effective immunity is the rise of the systemic levels of pro-inflammatory molecules during aging, establishing a chronic low-grade inflammation. Indeed, numerous alterations affecting directly or indirectly B cells in old people and mice are reminiscent of various effects of acute inflammation on this cell type in young adults. The present mini-review will highlight the possible adverse contributions of the persistent low-level inflammation observed in susceptible older organisms to the inadequate B-cell physiology.

Fcµ receptor as a Costimulatory Molecule for T Cells.

Fc receptor for IgM (FcµR)-deficient mice display dysregulated function of neutrophils, dendritic cells, and B cells. The relevance of FcµR to human T cells is still unknown. We show that FcµR is mostly stored inside the cell and that surface expression is tightly regulated. Decreased surface expression on T cells from elderly individuals is associated with alterations in the methylation pattern of the FCMR gene. Binding and internalization of IgM stimulate transport of FcµR to the cell surface to ensure sustained IgM uptake. Concurrently, IgM accumulates within the cell, and the surface expression of other receptors increases, among them the T cell receptor (TCR) and costimulatory molecules. This leads to enhanced TCR signaling, proliferation, and cytokine release, in response to low, but not high, doses of antigen. Our findings indicate that FcµR is an important regulator of T cell function and reveal an additional mode of interaction between B and T cells.