Iron overload impacts TCR γδ cell immunity Free

In this issue of Blood, Erdogdu et al¹ report that iron overload reduces circulating T-cell receptor (TCR) Vδ2 cells in hereditary hemochromatosis. Iron overload leads to constitutive stimulation of TCR Vδ2, triggering activation and exhaustion of these cells.

Hereditary hemochromatosis is a common disease of iron excess due to increased intestinal iron absorption and iron export from macrophages. The most frequent form of hereditary hemochromatosis is caused by HFE mutations. Functional HFE is critical for liver iron-sensing and hepcidin production. Hepcidin controls iron flux by binding and inducing the degradation of the iron exporter molecule ferroportin, which is present in enterocytes and macrophages. HFE hemochromatosis is a heterogeneous disease with low penetrance.² 

Iron is essential for immune responses, influencing pathogen survival, immune cell proliferation, and function. HFE hemochromatosis patients have lower numbers of invariant natural killer T and CD8⁺ T cells, which correlates with biochemical parameters of iron overload.^3-5 

In their study, Erdogdu et al first describe a consistent inversion of TCR Vδ chain usage in T cells isolated from the peripheral blood of patients with HFE hemochromatosis. The percentages of TCR γδ cells were similar between patients and healthy controls, but the ratio of TCR Vδ2⁺/TCR Vδ2⁻ cells was reduced in patients. Interestingly, the TCR Vδ2 cells showed impaired proliferative capacity when peripheral blood mononuclear cells were exposed to zoledronate. Zoledronate is an aminobisphosphonate that blocks farnesyl-pyrophosphate synthase and induces intracellular accumulation of isopentenyl pyrophosphate (IPP), a self-phosphoantigen.⁶ The accumulation of IPP is essential for the generation of butyrophilin (BTN) complexes that are known to interact and stimulate TCR Vγ9Vδ2. Briefly, the intracellular B30.2 domains of BTN2A1 and BTN3A1 recognize IPP, attaching to them.⁷ This binding leads to the formation of a larger complex formed by a BTN2A1 homodimer and a BTN3A1/BTN3A2 heterodimer that triggers a TCR Vγ9Vδ2–mediated activation.⁸ 

The study also gives new insights into the roles of iron in phosphoantigen generation and TCR Vδ2 cell proliferation. To address the function of iron, the authors were able to reject the possibility that iron chelates IPP, leading to a reduction in the stimulatory capacity of the antigen-presenting cell and subsequent proliferation of TCR Vδ2 cells. Another set of experiments showed that chelation of iron using deferoxamine abolished the proliferation of zoledronate-exposed TCR Vδ2 cells from healthy donors. Strikingly, the addition of exogenous Fe²⁺ induced the expansion of TCR Vδ2 cells from healthy donors similar to zoledronate in a BTN3A-dependent manner. Also, the authors show that iron reduced the transcription of alkaline phosphatases (ALPs) and suggest this as a reason for pyrophosphate accumulation in the antigen-presenting cell and increased stimulation of TCR Vγ9Vδ2 cells. Nevertheless, no data showed the reduction of ALP at the protein level or an augmented quantification of the cellular levels of IPP upon iron exposure.

Erdogdu et al raise new questions on the role of iron in phosphoantigen generation. Considering that iron increases the intracellular levels of IPP, it raises the question of whether, aside from the reduction of ALP, there is a modulation of the mevalonate pathway. This modulation could be either an induction of HMG-CoA reductase hyperactivity, which would result in increased IPP production, or, similar to aminobisphosphonates, a blocking of farnesyl-pyrophosphate synthase, preventing IPP from being used as a building block for farnesyl-pyrophosphate. A better understanding of this mechanism could provide valuable information on the generation of phosphoantigen and the pathologic contexts in which it may happen.

The iron-induced stimulation of TCR Vγ9Vδ2 cells had an impact in iron overload–related diseases such as HFE-related hemochromatosis and thalassemia. Although iron enhanced the proliferation of TCR Vγ9Vδ2 cells, the frequency of TCR Vδ2 cells was reduced in these diseases. The authors attribute this to: (1) the exhaustion of these cells caused by the persistent stimulation originating from iron overload; and (2) the increased apoptosis driven by FAS-FAS ligand interactions, because both FAS and FAS ligand were significantly more expressed on TCR Vδ2 cells from patients with hemochromatosis compared with healthy controls. Overall, both observations suggest a contraction of the TCR Vδ2 cells, which result from cellular exhaustion and activation-induced cell death.

The study highlights the importance of iron on the homeostasis of TCR Vδ2 cells. Due to the low penetrance of HFE hemochromatosis,² future studies should identify the level of iron storage required to impact the homeostasis of TCR Vδ2 cells.

This work by Erdogdu et al stands as an interesting observation with possible clinical implications because the exhaustion and proliferation impairment of TCR Vδ2 cell in pathologies with iron overload may compromise the known antitumor and anti-infection functions of TCR Vδ2 cells.

Conflict-of-interest disclosure: The authors declare no competing financial interests.