Abstract
In youth, thymic involution curtails production of new naïve T cells, placing the onus of T‐cell maintenance upon secondary lymphoid organs (SLO). This peripheral maintenance preserves the size of the T‐cell pool for much of the lifespan, but wanes in the last third of life, leading to a dearth of naïve T cells in blood and SLO, and contributing to suboptimal immune defense. Both keratinocyte growth factor (KGF) and sex steroid ablation (SSA) have been shown to transiently increase the size and cellularity of the old thymus. It is less clear whether this increase can improve protection of old animals from infectious challenge. Here, we directly measured the extent to which thymic rejuvenation benefits the peripheral T‐cell compartment of old mice and nonhuman primates. Following treatment of old animals with either KGF or SSA, we observed robust rejuvenation of thymic size and cellularity, and, in a reporter mouse model, an increase in recent thymic emigrants (RTE) in the blood. However, few RTE were found in the spleen and even fewer in the lymph nodes, and SSA‐treated mice showed no improvement in immune defense against West Nile virus. In parallel, we found increased disorganization and fibrosis in old LN of both mice and nonhuman primates. These results suggest that SLO defects with aging can negate the effects of successful thymic rejuvenation in immune defense.
Highlights
The thymus undergoes age‐related involution, that includes progressive loss of thymic epithelial and hematopoietic lineage cellularity, an increase in adiposity, and reduced T‐cell output (Hale, Boursalian, Turk, & Fink, 2006; Nikolich‐Žugich, 2014)
We examined the effects of (a) keratinocyte growth factor (KGF) administration in mice and nonhuman primates, or (b) sex steroid ablation (SSA) in mice using an antagonist of the luteinizing hormone‐releasing hormone receptor, degarelix (Firmagon)
Consistent with this, we found an improvement in thymocyte number following either KGF or SSA/degarelix treatment of old mice (Heng et al, 2012; Velardi et al, 2014) (Figure 1)
Summary
The thymus undergoes age‐related involution, that includes progressive loss of thymic epithelial and hematopoietic lineage cellularity, an increase in adiposity, and reduced T‐cell output (Hale, Boursalian, Turk, & Fink, 2006; Nikolich‐Žugich, 2014). Similar results have since been obtained using pharmacological sex steroid blockade as well as injection of growth factors (Heng et al, 2005; Min et al, 2007; Velardi et al, 2014) While some of these studies have shown some improvement in peripheral immune function in treated mice (Heng et al, 2012; Min et al, 2007), the ultimate tests of functional immunity in the face of microbial challenge were not performed. The question remains how well thymic rejuvenation improves the peripheral T‐cell pool with aging, and whether it confers improved protection against infection To address this question, we examined the effects of (a) keratinocyte growth factor (KGF) administration in mice and nonhuman primates, or (b) sex steroid ablation (SSA) in mice using an antagonist of the luteinizing hormone‐releasing hormone receptor, degarelix (Firmagon). These data indicate that restoration of thymic function by itself may not be sufficient to improve the immune response in elderly and suggest that interventions to simultaneously alleviate defects in aging SLO may need to be considered when designing strategies to improve immune response in older organisms
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