Insulin-Like Growth Factor I Is a Positive Regulator of Thymic Function.

The thymus is important in the recovery and maintenance of T-cell populations following hematopoietic stem cell transplantation. Neuroendocrine growth factors have been implicated in the regulation of thymocyte development and overall thymic function through direct effects on developing thymocytes and/or modulation of supporting thymic stroma. Insulin-like growth factor 1 (IGF-1) is a ubiquitously expressed mediator of cellular anabolic function that has been shown to affect the growth of primary and secondary immune organs. We present evidence supporting the role of IGF-1 as a regulator of thymic function in vivo. Recombinant human IGF-1 was administered into healthy young adult mice by continuous infusion for up to four weeks at a dose of 100 ug/day (5 mg/kg/day). During this period, thymic function was measured by multiple parameters including thymocyte number, thymocyte subset composition, thymic T-cell rearrangement circle (TREC) content, proliferation and developmental kinetics as measured by BrdU incorporation, peripheral naïve T-cell subsets, and peripheral TREC content. Two-week infusions of IGF-1 resulted in significant increases in thymic size, cellularity, and thymic TREC numbers. Within the earliest lineage-negative thymocyte subpopulations defined by CD44 and CD25 co-expression patterns, significant increases in the DN2 through DN4 subpopulations were observed. CD4+CD8+, CD4+CD8-, and CD4-CD8+ thymic populations were also uniformly increased with IGF-1 treatment. BrdU incorporation was increased in all thymocyte subsets with IGF-1 administration, suggesting a stimulatory effect of IGF-1 on thymocyte proliferation and developmental kinetics. In peripheral T-cell populations, significant increases in the number of CD4+ and CD8+ naïve cells were observed after four weeks of IGF-1 treatment. The expansion of peripheral naïve cell populations occurred in the absence of increased cell division as measured by Ki67 expression. On the other hand, significant increases in total peripheral TREC numbers were observed at this time, indicating an increase in the number of recent thymic emigrants with IGF-1 administration. IGF-1 receptor (IGF-1R) is expressed on both thymocytes and peripheral T-cells. Mice constitutively homozygous for null mutations of IGF-1R die at birth. Consequently, to assess the role of IGF-1R signaling on thymic function and T-cell homeostasis, mice lacking IGF-1R specifically on thymocytes and T-cells were generated by cre recombinase mediated deletion of the IGF-1R high-affinity binding site (LCK-Cre/lox-IGF1R). Compared to cre-negative littermates, LCK-Cre/lox-IGF1R mice exhibited a 50% decrease in thymocyte cellularity that is due almost entirely to decreases in the CD4+CD8+ double-positive thymocyte population and in the lineage-negative DN4 subpopulation. The size of the CD4+CD8- and CD4-CD8+ thymocyte populations were not affected. Thymic TREC numbers were also decreased by 50%. Diminished thymic output in LCK-Cre/lox-IGF1R mice was manifested by a decrease in the size of splenic naïve CD4+ and CD8+ populations and splenic TREC numbers. These results demonstrate that: 1) administration of IGF-1 enhances thymic function through the expansion of thymocyte subpopulations and thymic output; and 2) IGF-1R signaling is important in the maintenance of thymocyte and peripheral T-cell populations. These findings support the concept of IGF-1 as a potentially useful agent in facilitating T-cell reconstitution following hematopoietic stem cell transplant.