In a new study, thymic tissue implanted in the spleen improved immune responses against viruses and tumors and reversed age-related thymic involution in mice [1].
Growing one organ inside another
The thymus is a small but crucial organ, where T cells mature to become the backbone of our adaptive immune system. There, they acquire their ability to recognize diverse threats along with mechanisms that stop them from attacking the body’s own cells (self-tolerance).
Unfortunately, as we age, the thymus undergoes involution, the progressive loss and disorganization of functional tissue [2]. Chemotherapy, radiation, infections, and other stresses can also damage it. Some children are born without functional thymi, and some patients have their thymi removed.
Existing approaches try to stimulate the remaining thymus tissue or reconstruct the organ using cellular therapies and engineered tissues. However, the task becomes especially difficult when the organ is absent or severely damaged.
Transplantation offers another way: donor thymic tissue can become a new site of T-cell development elsewhere in the body. Cultured thymus tissue implanted into thigh muscle is already used to restore immunity in children with congenital thymic deficiency, but recovery is slow and often incomplete [3].
In a new study published in Advanced Science, a group of Chinese scientists suggests a novel approach: growing thymic tissue in the spleen. This organ has a rich blood supply and hosts a lot of immune cells. Other splenic cells secrete useful growth signals and extracellular matrix. The organ can even support the production of blood cells under certain conditions and is especially immune-tolerant, which makes it the perfect destination for allogeneic (foreign) transplants.
Almost like a normal thymus
The researchers began with neonatal thymus tissue from C57BL/6J mice. Recipients were young BALB/c nude mice, which lack normal thymic development and have profound T-cell deficiency.
Thymus transplantation caused severe adverse reactions by the host’s body (graft-versus-host disease). Thymic tissues contain many developing T cells, so the authors first needed to remove these potential attackers while preserving the tissue itself.
Having established the transplantation protocol, the researchers implanted cultured thymic fragments into either the spleen or quadriceps muscle. Thymic fragments grew faster and formed organized tissue earlier in the spleen. By two weeks, splenic grafts already contained distinct cortical and medullary regions – the two major thymic compartments that support different stages of T-cell development. Muscle grafts were smaller, less organized, and partly necrotic.
Both graft types grew, but splenic grafts reached approximately half the normal thymus weight, much more than muscle grafts. The latter eventually developed a recognizable cortical and medullary organization but remained smaller.
The spleen expressed more thymic development factors and contained more relevant precursor cells than muscle. It also expressed more hemoglobin, consistent with its rich blood supply. However, the study does not show how much each of these factors contributed to the spleen’s superiority compared to muscle.
Circulating T cells appeared after splenic transplantation, and their numbers increased until approximately week eight. However, total T-cell counts remained substantially below normal controls. Recovery was stronger for CD8+ cells than for CD4+ cells, whose counts stabilized at approximately half the control level.
T cells from recipients of splenic drafts proliferated at levels comparable to controls. When challenged with ovalbumin, an antigen often used in such experiments, treated mice developed antigen-responsive cells, unlike untreated nude mice. Importantly, the response was triggered by the host’s own antigen-presenting cells. Regenerated CD4+ T cells also showed a broad receptor repertoire: they were successfully “educated” to counter a wide range of pathogens.
Splenic graft recipients developed less graft-versus-host disease than muscle-graft recipients. Histology, measurements of liver functions, and several inflammatory markers did not reveal major injury. Having established the method in animals lacking a functional thymus, the authors moved to naturally aged mice, transplanting neonatal thymus fragments into 20-month-old animals of the same genetic background. Splenic grafts grew and formed organized thymic tissue in aged recipients. They were larger and had more developing T cells than muscle grafts. Naïve T-cell counts improved relative to controls.
Effective response to infections and cancer
The authors returned to the original nude-mouse model to see whether T-cell restoration translated into protection from infections. Following vesicular stomatitis virus infection, graft recipients had activated T cells and controlled infection much better than untreated nude mice. At ten days, splenic-graft recipients had less detectable viral material and less injury, broadly resembling immunocompetent controls.
The researchers then challenged the mice with tumor cells. Splenic graft recipients demonstrated restricted growth of B16 melanoma compared with untreated nude mice. Their tumors were smaller and contained more infiltrating T cells, with outcomes broadly resembling those of normal controls.
The researchers also implanted human HCT116 colorectal cancer cells. Tumors formed in all untreated nude mice but in none of the splenic-graft recipients, whose level of rejection resembled that of immunocompetent mice.
Finally, the researchers asked whether the effect extended to human tissue. They used immunodeficient mice that had received cryopreserved human thymic fragments and human blood-forming stem cells from the same donor. Groups received no transplant, thymus alone, stem cells alone, or stem cells combined with thymus implanted into spleen or muscle.
Human thymic tissue survived and retained organized architecture in the spleen more effectively than in the muscle. Muscle grafts frequently had necrotic regions, and some became undetectable. Thymus-only recipients produced few circulating human T cells, while adding human stem cells resulted in much stronger T-cell reconstitution.
Literature
[1] Wang, S., Zhang, Z., Dai, F., Yin, Z., Xing, Z., Li, Y., … & Dong, L. (2026). Intrasplenic Thymus Organogenesis from Injectable Tissue Fragments Restores Functional T‐Cell Immunity. Advanced Science, e77358.
[2] Liang, Z., Dong, X., Zhang, Z., Zhang, Q., & Zhao, Y. (2022). Age‐related thymic involution: Mechanisms and functional impact. Aging cell, 21(8), e13671.
[3] Markert, M. L., Boeck, A., Hale, L. P., Kloster, A. L., McLaughlin, T. M., Batchvarova, M. N., … & Mahaffey, S. M. (1999). Transplantation of thymus tissue in complete DiGeorge syndrome. New England Journal of Medicine, 341(16), 1180-1189.
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