The link between the differentiation of effector T lymphocytes and metabolism has become an important area of research. The role played by the phosphoinositide 3-kinase (PI3K)/Akt/mTOR (mammalian target of rapamycin) pathway in this process was recently emphasized by Lucas et al.1 who reported a series of primary immunodeficiency patients with three different germ-line, gain-of-function mutations of the p110δ subunit of PI3K. The patients consistently presented a deficiency in naive T lymphocytes and an accumulation of highly differentiated effector T cells. This phenotype was associated with recurrent respiratory infections and with the reactivation of persistent viruses. The disease was named PASLI (p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency). The same disorder was simultaneously reported by Angulo et al.2 and was named the activated PI3K-δ syndrome (APDS). Although the accumulation of effector T cells in the state of immunodeficiency was somewhat unexpected, the description of this syndrome provides important insight into the regulation of T-cell differentiation and T-cell memory.
The PI3K mutations were identified by Lucas et al. in nine patients from seven unrelated families from different ethnic backgrounds. All patients had presented childhood onset sinopulmonary infections. Most patients had lymphadenopathies and nodular lymphoid hyperplasia at mucosal surfaces. Epstein–Barr virus viremia was detected in all patients and cytomegalovirus viremia in some, indicating a reduced control of persistent virus replication. Lymphoma was diagnosed in two patients. Similar clinical signs were observed in the series of 17 PASLI/APDS patients reported by Angulo et al.2 In the two studies, whole-exome sequencing was used to identify specific mutations. In exome sequencing, only the exons, i.e., the parts of the gene sequences that code for the mature RNA, are sequenced thereby reducing significantly the amount of DNA that needs to be analyzed. Lucas et al. identified three germline-encoded gain-of-function mutations, each located within a different domain of the p110δ subunit of PI3K (encoded by the PIK3CD gene).1 One of the mutations (E1021K) was also identified by Angulo et al.2 Based on a comparison with the described mutations of the PI3K catalytic subunit p110α within cancer cells, Lucas et al. proposed that the E1021K mutation would result in enhanced membrane binding.1 This was confirmed experimentally by Angulo et al.2 T cells from PASLI/APDS patients exhibited increased levels of PIP3, together with elevated Akt phosphorylation and FOXO1 degradation. These were accompanied by increased phosphorylation of mTORC1 target genes and increased glucose uptake (Figure 1, red arrows).1,2 In contrast, other T-cell receptor (TCR) signaling pathways such as TCR-induced Ca2+ flux were not affected by the PIK3CD mutations.1 These alterations in the PI(3)K/Akt/mTORC1/FOXO1 pathways were associated with CD4 T-cell cytopenia and with normal to high CD8 T-cell counts.1 Importantly, PASLI/APDS patients had reduced frequencies of naive cells and an accumulation of effector and highly differentiated RA+ effector memory cells within both the CD4 and the CD8 T-cell subsets. The accumulation within the PASLI/APDS patients of CD8 T cells with a highly differentiated phenotype was associated with decreased proliferative responses and IL-2 production following TCR activation and with high production of IFN-γ and cytolytic molecules.1 Although some of these functional properties were assessed using in vitro expanded T-cell lines and not directly ex vivo, they are consistent with the marked differentiation towards effector cells. Somewhat different results were reported by Angulo et al.2 who observed a reduced production of IFN-γ by CD8 T cells of PASLI/APDS patients. This difference may be related to the fact that Lucas et al. measured cytokine production by flow cytometry following short-term stimulation, whereas Angulo et al. measured cytokines in supernatants following several days of stimulation. In the latter conditions, the amount of cytokines produced is influenced by cell proliferation that was shown to be defective in both reports. In addition, Angulo et al.2 reported that the constitutive activation of the PI3K pathway also resulted in an increased susceptibility of T cells to activation-induced cell death and could thereby limit the expression of effector functions. Inhibition of mTOR by the administration of rapamycin to one PASLI/APDS patient decreased CD8 T-cell counts and increased the proportions of naive and central memory T cells in the CD4 T-cell compartment. Although the reason for the different impact of PIK3CD mutations and rapamycin treatment on CD4 and CD8 T-cell subsets remains unclear, these observations are in keeping with the results obtained in the mouse and non-human primate, where rapamycin was shown to promote virus-specific memory CD8 T-cell responses.6 Together, these results suggest that mTOR inhibition may be an effective strategy to improve memory T-cell responses to vaccines and infectious pathogens in humans.
This is a preview of subscription content, access via your institution
