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Adenosine monophosphate deaminase 3 null mutation causes reduction of naive T cells in mouse peripheral blood
Xiaoming Zhan1, Xue Zhong1, Jin Huk Choi1
1Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX.
Abstract:
Adenosine monophosphate deaminase 3 (Ampd3) encodes the erythrocyte isoform of the adenosine monophosphate (AMP) deaminase gene family. Mutations in this gene have been reported in humans, leading to autosomal-recessive erythrocyte AMP deaminase deficiency. However, the mutation is considered clinically asymptomatic. Using N-ethyl-N-nitrosourea mutagenesis to find mutations that affect peripheral lymphocyte populations, we identified 5 Ampd3 mutations (Ampd3guangdong, Ampd3carson, Ampd3penasco, Ampd3taos, and Ampd3commanche) that strongly correlated with a reduction in naive CD4+ T and naive CD8+ T-cell populations. Causation was confirmed by targeted ablation of Ampd3. Knockout mice had reduced frequencies of CD62LhiCD44lo CD4+ naive and CD8+ naive T cells. Interestingly, these phenotypes were restricted to T cells circulating in peripheral blood and were not seen in T cells from secondary lymphoid organs (lymph nodes and spleen). We found that reduction of naive T cells in the peripheral blood of Ampd3-/- mice was caused by T-cell-extrinsic factor(s), which we hypothesize to be elevated levels of adenosine triphosphate released by Ampd3-deficient erythrocytes. These findings provide an example in which disruption of an erythrocyte-specific protein can affect the physiological status of lymphocytes in peripheral blood.
Insights
Mutations in Adenosine monophosphate deaminase 3 (Ampd3) impact T-cell populations. Ampd3 deficiency in red blood cells may affect circulating naive T cells in peripheral blood.
Area of Science:
- Immunology
- Hematology
- Genetics
Background:
- Adenosine monophosphate deaminase 3 (Ampd3) is an erythrocyte-specific enzyme.
- Mutations in Ampd3 are linked to erythrocyte AMP deaminase deficiency in humans, though considered asymptomatic.
- The role of Ampd3 in lymphocyte physiology is not well understood.
Purpose of the Study:
- To investigate the role of Ampd3 in peripheral lymphocyte populations.
- To identify mutations affecting T-cell populations using genetic screening.
- To elucidate the mechanism by which Ampd3 deficiency impacts T cells.
Main Methods:
- N-ethyl-N-nitrosourea mutagenesis was used to screen for mutations affecting peripheral lymphocytes.
- Five novel Ampd3 mutations were identified and correlated with reduced naive T-cell populations.
- Targeted gene ablation was performed to create Ampd3 knockout mice.
- Flow cytometry was used to analyze T-cell populations in peripheral blood and lymphoid organs.
Main Results:
- Five Ampd3 mutations were identified, strongly correlating with reduced naive CD4+ and CD8+ T-cell frequencies.
- Ampd3 knockout mice exhibited decreased percentages of naive CD4+ and CD8+ T cells (CD62LhiCD44lo) in peripheral blood.
- These T-cell phenotypes were specific to peripheral blood and absent in secondary lymphoid organs.
- The reduction in naive T cells was attributed to T-cell-extrinsic factors, potentially elevated ATP from Ampd3-deficient erythrocytes.
Conclusions:
- Ampd3 plays a role in regulating naive T-cell populations in peripheral blood.
- Erythrocyte Ampd3 deficiency can influence lymphocyte homeostasis via T-cell-extrinsic mechanisms.
- This study highlights an interplay between erythrocyte function and peripheral T-cell physiology.
