Defective T-helper cell function after T-cell–depleting therapy affecting naive and memory populations

Abstract

IntroductionSevere immune dysfunction is a predictable consequence of high-dose anticancer chemotherapy with or without autologous or allogeneic stem cell support and results in significant morbidity and mortality in potentially curable diseases. [1][2][3] One obvious explanation for such immune dysfunction is a depletion of immune cells by the cytotoxic effects of anticancer drugs. 4,5 However, even after quantitative regeneration immune cells do not regain full immune competence for a prolonged period of time. [6][7][8][9][10] T cells play a key role in multiple immune responses. Therefore, both a depletion and a disturbed function caused by cytotoxic anticancer treatment are potentially harmful to the immune surveillance of the host, including an increased susceptibility to infections with otherwise less harmful pathogens. [11][12][13][14][15] T-cell reconstitution after cytotoxic therapy does not repeat fetal T-cell ontogeny. [16][17][18][19] In fact, the first T cells that repopulate the host after T-cell depleting (TCD) therapy expand extrathymically from peripheral residual T cells whereas a thymus-dependent T-cell regeneration is delayed and may be even incomplete in adult patients in whom thymic function has declined. [20][21][22] Extrathymically expanded T cells bear a memory phenotype, 23 as their expansion is determined by antigenic stimulation. 24 Their capacity to restore full T-cell function is believed to be limited, because of (1) skewing of the T-cell repertoire 25-27 and (2) an increased susceptibility to apoptosis, including activation-induced apoptosis. 28 In contrast, T cells with a naive phenotype presumably represent recent thymic emigrants, 23,[29][30][31] having matured from precursors via thymopoiesis, and thus may be spared from the postchemotherapy immune dysfunction.To test this hypothesis we investigated by flow cytometry the in vitro immune function of distinct naive (CD4 ϩ CD45RA ϩ ) and memory (CD4 ϩ CD45RA Ϫ ) T-helper cells. Examinations were performed at one to 3 months after completion of TCD therapy, a time point at which CD4 ϩ CD45RA ϩ T cells were readily detectable but not yet fully recovered.Upon stimulation with polyclonal mitogens in vitro we found a reduced up-regulation of the early activation-induced cell surface molecule, CD69, detectable in CD4 ϩ T cells even in the presence of exogenous interleukin 2 (IL-2). Strikingly, CD4 ϩ CD45RA ϩ cells were similarly affected as CD4 ϩ CD45RA Ϫ cells by decreased stimulatory responses and an increased susceptibility to apoptosis as detected by annexin V staining. 32,33 When peripheral blood mononuclear cell (PBMC) populations were enriched for T cells, the stimulatory responses improved markedly. Together, the findings are consistent with a concept that factors external to T cells, eventually affecting T-helper cells irrespective of a naive or memory phenotype, contribute to the prevailing T-cell dysfunction in the early post-TCD therapy period. Patients, materials, and methods PatientsT-cell analyses in pediatric patients ...

Monocyte-mediated T-cell suppression and augmented monocyte tryptophan catabolism after human hematopoietic stem-cell transplantation

“…20 Both were found in this study cohort. PBMCs of 15 HSCT recipients contained reduced proportions and numbers of T cells (median 40%, or 0.32 ϫ 10 9 cells/L [range 0.06 to 1.06] whole blood), compared with healthy controls older than 10 years of age (normal range 55%-82%, or 1.0 ϫ 10 9 -3.9 ϫ 10 9 cells/L).…”

“…One prominent defect in T cells after HSCT is an increased susceptibility to apoptosis, 20,25,26 and induction of T-cell apoptosis is one effect of accelerated tryptophan catabolism. 28,49 Thus, we determined whether post-HSCT monocytes contributed to the enhanced rate of apoptosis in post-HSCT T cells.…”

“…[16][17][18] Dysfunction of T cells, frequently observed as a decreased lymphoproliferative response to activation, 16 has been attributed to numerous defects intrinsic to T cells. These include inappropriate cellular activation 19,20 and disturbed cytokine production, 21,22 especially of interleukin 2 (IL-2), 23,24 and increased susceptibility to apoptosis. 25,26 Here, we show that an impaired T-cell proliferative capacity early after HSCT may be mediated by potent suppressor activity of monocytes.…”

“…These purified normal donor T cells gave a similar proliferative response to anti-CD3, whether they were cultured alone (86 ϫ 10 Ϫ3 cpm) or in the presence of post-HSCT monocytes (91 ϫ 10 Ϫ3 cpm). Since control T-cell responses were not reduced by coculture with post-HSCT monocytes, we conclude that monocyte-mediated T-cell inhibition after HSCT involves both a suppressor effect of post-HSCT monocytes and a susceptibility of post-HSCT T cells to this suppression.One prominent defect in T cells after HSCT is an increased susceptibility to apoptosis, 20,25,26 and induction of T-cell apoptosis is one effect of accelerated tryptophan catabolism. 28,49 Thus, we determined whether post-HSCT monocytes contributed to the enhanced rate of apoptosis in post-HSCT T cells.…”

Ambivalent effects of dendritic cells displaying prostaglandin E2‐induced indoleamine 2,3‐dioxygenase

“…For DC maturation, iDCs were exposed to a cytokine mix containing of IL-1β (1 × 10 4 U/mL), IL-6 (10 3 U/mL), TNF-α (10 3 U/mL) (all PeproTech) in the presence or absence of PGE 2 (1 μg/mL) (Sigma-Aldrich, St. Louis, MO, USA) for 48 h. In some experiments, iDCs were matured with 50 ng/mL LPS (Calbiochem, La Jolla, CA, USA) and 1000 U/mL IFN-γ (Boehringer Ingelheim, Ingelheim, Germany). The DC quality was monitored by visual and flow cytometric evaluation of a typical DC morphology and expression of cell-surface markers, respectively.Highly enriched T cells were prepared as described [56]. In brief, total CD3 + T cells were isolated from total PBMCs by magnetic cell sorting (Miltenyi Biotec Inc., Bergisch Gladbach, Germany) according to manufacturer's instructions, routinely resulting in a greater than 95% enrichment of the targeted cell population.…”