PD-1⁺memory phenotype CD4⁺T cells expressing C/EBPα underlie T cell immunodepression in senescence and leukemia

Abstract

Although altered T cell function plays a part in immunosenescence, the mechanisms remain uncertain. Here we identify a bona fide age-dependent PD-1 ؉ memory phenotype (MP) CD4 ؉ T cell subpopulation that hardly proliferates in response to T cell receptor (TCR) stimulation and produces abundant osteopontin at the cost of typical T cell lymphokines. These T cells demonstrate impaired repopulation in Rag2 ؊/؊ mice, but a homeostatic proliferation in ␥-ray-irradiated mice. These T cells also reveal a unique molecular signature, including a strong expression of C/EBP␣ normally expressed in myeloid-lineage cells, with diminished c-Myc and cyclin D1. Transduction of Cebpa in regular CD4 ؉ T cells inhibited the TCR-mediated proliferation with c-Myc and cyclin D1 repression and caused a striking activation of Spp1 encoding osteopontin along with concomitant repression of T cell lymphokine genes. Although these T cells gradually increase in number with age and become predominant at the senescent stage in normal mice, the generation is robustly accelerated during leukemia. In both conditions, their predominance is associated with the diminution of specific CD4 ؉ T cell response. The results suggest that global T cell immunodepression in senescence and leukemia is attributable to the increase in PD-1 ؉ MP CD4 ؉ T cells expressing C/EBP␣.immunosenescence ͉ osteopontin

Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2

“…More importantly, neutralizing antibodies to PD-L1 or PD-1 can improve disease status and are now being used in clinical trials. Furthermore, it was recently elucidated that PD-1 is expressed on several unique T cell subsets, exhausted T cells (Janssen et al, 2003;Barber et al, 2006;Day et al, 2006), regulatory T (T reg) cells , and senescent T cells (Shimatani et al, 2009). All these T cells expressing PD-1 has been shown to exist in an unresponsive or anergic state.…”

The PD-1/PD-L1 axis contributes to T-cell dysfunction in chronic lymphocytic leukemia

“…[18][19][20] On the contrary, PD-1 is classically considered a marker of cell exhaustion in the CD8 subset. 21 Thus, the finding of an increased expression of PD-1 in T lymphocytes from CLL patients suggests a relative enrichment in terminally differentiated cells as compared to controls with a similar age.…”

T Cell Senescence and Autoimmunity

“…We previously proposed that the increase of SA-T cells chronically with age and acutely with a leukemic condition might be related to the decrease of T cell genesis due to physiological thymic involution and leukemia-associated T-lymphocytopenia, respectively [ 6 ]. In a lymphopenic condition, the peripheral CD4 + T cells undergo homeostatic proliferation, which depends on homeostatic cytokines and tonic TCR-signal via MHC II-bearing self-peptides [ 5 ].…”

“…It is suggested that these MP T cells include those that have homeostatically expanded in response to the decreasing drift of the T cell numbers, in addition to the authentic memory T cells for specifi c environmental antigens [ 5 ]. We reported that a unique PD-1 + MP CD4 + T cell population is increased with age [ 6 ], now termed senescence-associated (SA-) T cells (Fig. 1b ).…”

“…1b ). The SA-T cells showed compromised capacity of clonal proliferation and production of typical T cell-specifi c cytokines via TCR-stimulation; however, the SA-T cells secrete abundant proinfl ammatory cytokines such as osteopontin (OPN) [ 6 ].…”