Massive expansion of maternal T cells in response to EBV infection in a patient with SCID-Xl

To the editor:

X-linked severe combined immunodeficiency (SCID-Xl) is caused by defects in IL2RG, the gene encoding the IL-2 receptor γ chain. Accounting for 50% to 60% of cases of SCID,¹  it SCID-XI is typically characterized by an absence of mature T and natural killer (NK) lymphocytes, whereas native B cells are detectable and are present in increased numbers. Viral infection caused by Epstein-Barr virus (EBV) in SCID patients can lead to fulminant and often fatal B-cell lymphoproliferative disease, similar to those occurring in immunosuppressed organ-transplant recipients.^2-4 

A 3-month-old boy, born to nonconsanguineous parents, was referred to our center for investigation of a rapidly progressive hepato-splenomegaly without peripheral lymphadenopathy. Chest x-rays revealed an absence of thymic shadow. Liver and spleen were found homogeneously enlarged by ultrasound examination. Whole blood count showed a marked lymphocytosis (up to 100 × 10⁹/L) that consisted of CD3⁺CD8⁺TCRαβ HLA-DR⁺ activated cells with a complete absence of CCR7⁺CD45RA⁺CD8⁺ and CD4⁺CD45RA⁺CD31⁺ naive T cells (Figure 1A). The T-cell repertoire, as evaluated by immunoscope,⁵  showed an increase in Vβ5, Vβ12, Vβ14, and Vβ17 TCR usage among CD8⁺ cells (Figure 1C). Those features led us to investigate for the existence of a SCID. The maternal origin of the circulating T and NK cells was confirmed by FISH analysis of the CD3⁺ and CD56⁺ cell fraction, respectively, which were obtained by cell sorting. There was no engraftment of maternal stem cells, as verified by FISH analysis of the polymorphonuclear neutrophils. SCID-Xl was confirmed by gene sequencing of IL2RG on the patient's genomic DNA that revealed a previously described R226C mutation. The mother carried the mutation.

An EBV infection was diagnosed by amplification of the viral DNA in blood samples by polymerase chain reaction with a whole blood viral load of 6 log₁₀ DNA copies/mL. The child's mother displayed a serologic profile of past EBV infection (ie, IgG anti-VCA and IgG anti-EBNA positive). We investigated the possible role of this ongoing viral infection as a trigger for the extreme lymphocytosis, the latter being reminiscent of the one observed during infectious mononucleosis.^6-8  Interestingly, in vitro stimulation of lymphocytes with LMP2-A, but neither with BZLF-2 nor EBNA-1, induced a significant activation of CD8⁺ T cells as shown by detection of intracytoplasmic interferon γ (IFN-γ) by flow cytometry. The same test, performed on the mother's circulating T cells, did not detect LMP2-A specific in vivo activated T cells, a result that is not surprising in the absence of active EBV infection (Figure 1D). This result indicates a major expansion of LMP2-A specific maternal T cells in the patient's blood secondary to EBV infection.

The EBV infection was treated by rituximab infusions until the EBV viral load became undetectable by PCR. The hepato-splenomegaly gradually regressed secondary to this therapy associated with a short course of steroids. A liver biopsy, performed 4 weeks after initiation of therapy, showed an infiltration of the portal and lobular area by T lymphocytes that were mostly CD8⁺ with a granzyme B–positive staining (Figure 1B). The Epstein-Barr virus–encoded small RNA (EBER) staining was negative.

Transplacental-acquired maternal T cells have already been reported to cause allograft rejection and immune cytopenias.⁹  To the best of our knowledge, this is the first report of “natural” adoptive immunity toward EBV with a massive in vivo expansion of maternal engrafted T cell conferring specific immunity against this virus that may account for the patient's survival and relative control of EBV-driven B-cell proliferation.