Submitted April 5, 2006
Accepted May 18, 2006
Expression of LAG-3 by tumor-infiltrating lymphocytes is
co-incident with the suppression of latent membrane
antigen-specific CD8+ T-cell function in
Hodgkin lymphoma patients
Maher K Gandhi, Eleanore Lambley, Jaikumar Duraiswamy, Ujjwal Dua, Corey Smith, Suzanne Elliott, Devinder Gill, Paula Marlton, John Seymour, and Rajiv Khanna*
Tumor Immunology Laboratory,Division of Infectious Diseases,Queensland Institute of Medical Research
Department of Haematology, Princess Alexandra Hospital, Brisbane, Australia
Haematology Service, Peter MacCallum Cancer Centre & University of Melbourne, Australia
* Corresponding author; email: rajiv.khanna{at}qimr.edu.au.
In Hodgkin' s Lymphoma (HL) the malignant Hodgkin Reed-
Sternberg (HRS) cells comprise only 0.5-10% of the
diseased tissue. The surrounding cellular infiltrate in
enriched with T-cells which are hypothesized to modulate
anti-tumor immunity. We show that a marker of regulatory
T-cells, LAG-3 is strongly expressed on infiltrating
lymphocytes present in proximity to HRS cells.
Circulating regulatory T-cells (CD4+CD25hiCD45ROhi,
CD4+CTLA4hi and CD4+LAG-3hi) were elevated in HL
patients with active disease when compared to remission.
Longitudinal profiling of EBV-specific CD8+ T-cell
responses in 94 HL patients revealed a selective loss of
interferon-gamma expression by CD8+ T-cells specific for
latent membrane proteins (LMP) 1 and 2, irrespective of
EBV tissue status. Intra-tumoral LAG-3 expression was
associated with EBV tissue positivity, whereas FOXP3 was
linked with neither LAG-3 or EBV tissue status. The
level of LAG-3 and FOXP3 expression on the tumor-
infiltrating lymphocytes was co-incident with impairment
of LMP1/2-specific T-cell function. In vitro pre-
exposure of peripheral blood mononuclear cells to HRS
cell-line supernatant significantly increased the
expansion of regulatory T-cells and suppressed LMP-
specific T-cell responses. Deletion of CD4+ LAG-3+ T-
cells enhanced LMP-specific immunity. These findings
indicate a pivotal role for regulatory T-cells and LAG-3
in the suppression of EBV-specific cell-mediated
immunity in HL.
