Latent CMV and the CD4+ T Cell Transcription Program in Patients with Chronic GVHD

Latent CMV infection is known to have a life long effect on the distribution of T cell subsets, but little is known about the impact on cell function. We performed a gene expression analysis in purified CD4+ T cells from 68 hematopoietic cell transplant (HCT) recipients (median age 48; range 20-65) studied on average 5 years after HCT (median 4.75; range 1-20 years). The study population included 38 patients with active chronic GVHD (cGVHD) and 30 tolerant (TOL) patients. Tolerance was defined by absence of signs, symptoms of cGVHD and immunosuppressive therapy (IST) for 3 months. Gene expression was measured on Illumina bead arrays. CMV status was defined by pre-transplant recipient CMV serology (by ELISA). There was no recorded evidence of CMV reactivation at the time of study. Nine of 93 candidate genes associated with immune function and inflammation were found to be associated CMV serostatus in cGVHD patients at a significance threshold of p<0.05, but only four genes (ITK; CD86; PLCG1; PIK3CB) were associated with CMV serostatus in TOL patients. A multivariate analysis including: acute GVHD, conditioning regimen, marrow vs. PBSC; related vs. unrelated donor, matched vs. mismatched donor, recipient age and time post-HCT was performed Table 1. cGVHD patients had a profile consistent with T effector cell activation that was not present in TOL. The characteristic inflammatory environment, increased cytokine production, immunosuppressive therapy and impaired T cell immune reconstitution observed in cGVHD, may increase the risk of CMV reactivation and subsequent upregulation of genes related to T cell activation and effector functions. In contrast, tolerant patients may have achieved greater immune reconstitution and more effective CMV surveillance and control. T cell activation during cGVHD is a complex process that appears to be influenced by latent CMV.Tabled 1Table 1. Multivariate analysisActive cGVHDTolerantCMV+ (n = 17) vs CMV-(n = 21)CMV+ (n = 11) vs CMV-(n = 19)ITK0.023↑upregulated geneCD860.034↑PLCG10.033↑PIK3CB0.005↑GZMB0.024↑INFg0.015↑IL4R0.025↓downregulated genePTPN70.000↑PRF10.000↑GZMA0.003↑PDCD10.008↑IL12RB1a0.016↑IL12RB1b0.000↑↓ downregulated gene↑ upregulated gene Open table in a new tab