Background & Aims There is an unclear relationship between T-cell expression of inhibitory receptors and their ability to control viral infections. Studies of human immune cells have been mostly limited to T cells from blood, which is not always the site of infection. We investigated the relationship between T-cell location, expression of inhibitory receptors, maturation, and viral control using blood and liver cells from patients with hepatitis C virus (HCV) and other viral infections. Methods We analyzed 36 liver samples from HCV antibody-positive patients (30 from patients with chronic HCV infection, 5 from patients with sustained virologic responses [SVRs] to treatment, and 1 from a patient with spontaneous clearance), with 19 paired blood samples, and 51 liver samples from HCV-negative patients, with 17 paired blood samples. Intrahepatic and circulating lymphocytes were extracted; T-cell markers and inhibitory receptors were quantified, for total and virus-specific T cells, by flow cytometry. Results Levels of the markers PD-1 and 2B4 (but not CD160, TIM3, or LAG3) were increased on intrahepatic T cells from healthy and diseased liver tissues, compared to T cells from blood. HCV-specific intrahepatic CD8+ T-cells from patients with chronic HCV infection were distinct in that they expressed TIM3 along with PD1 and 2B4. In comparison, HCV-specific CD8+ T cells from patients with SVRs and T cells that recognized cytomegalovirus (CMV) lacked TIM3, but expressed higher levels of LAG3; these cells also had different memory phenotypes and proliferative capacity. Conclusions T cells from liver express different inhibitory receptors than T cells from blood, independent of liver disease. HCV-specific and CMV-specific CD8+ T cells can be differentiated based on their expression of inhibitory receptors; these correlate with their memory phenotype and levels of proliferation and viral control.

Chronic lymphocytic leukemia (CLL) patients who develop Hodgkin lymphoma (HL) have limited survival. No current therapeutic standard of care exists. We conducted a multi-center retrospective study of patients with Hodgkin Transformation (HT) of CLL. Clinicobiologic characteristics, treatment type, and survival outcomes were analyzed and compared with historic case series. Ninety-four patients were identified. Median age at HT was 67 years (range, 38-85). Median time from CLL diagnosis to HT was 5.5 years (range, 0-20.2). Prior to HT, patients received a median of 2 therapies for CLL (range, 0-12). As initial therapy for HT, 61% (n=62) received ABVD-based regimens (adriamycin, bleomycin, vinblastine, and dacarbazine). Seven (7%) patients received hematopoietic cell transplantation (HCT) while in first complete remission (CR1). The median number of treatments for HT per patient was 1 (range, 0-5) with 59 (61%) patients only receiving one line of therapy. After HT, patients had a median follow-up of 1.6 years (range, 0-15.1). Two-year overall survival (OS) after HT diagnosis was 72% (95%CI 62-83%). The patients who received standard ABVD-based therapy had a median OS of 13.2 years. Although limited by small sample size, the patients who underwent HCT for HT in CR1 had a similar 2-year OS (n=7; 67%) compared to patients who did not undergo HCT for HT in CR1 (n=87; 72%; p=0.46). In this multi-center study, HT patients treated with ABVD-based regimens had prolonged survival supporting the use of these regimens as standard of care for these patients.

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