Antigen Selection Shapes the T-cell Repertoire in Chronic Lymphocytic Leukemia.
OBJECTIVE
The role of antigen(s) in shaping the T-cell repertoire in chronic lymphocytic leukemia, although relevant for understanding malignant cell interactions with cognate T cells, is largely unexplored.


METHODS
Here we profiled the T-cell receptor β chain gene repertoire in 58 chronic lymphocytic leukemia patients, focusing on cases assigned to well-characterized subsets with stereotyped clonotypic B-cell receptor immunoglobulins, therefore those cases most evidently selected by antigen (subsets #1, #2, and #4).


RESULTS
Remarkable repertoire skewing and oligoclonality were observed, and differences between subsets were noted regarding both T-cell receptor β chain gene usage and the extent of clonality, with subset #2 being the least oligoclonal. Longitudinal analysis of subset #4 cases revealed that although the repertoire may fluctuate over time, certain clonotypes persist, thus alluding to persistent antigenic stimulation. Shared ("stereotyped") clonotypes were found between different patients, reflecting selection by common antigenic elements. Cross-comparison of our dataset with public databases showed that some T-cell clonotypes may have expanded secondary to common viral infections; however, the majority of clonotypes proved to be disease-specific.


CONCLUSIONS
Overall, the T-cell receptor β chain repertoire in chronic lymphocytic leukemia is likely shaped by antigen selection and the implicated antigenic elements may concern epitopes that also select the malignant B-cell progenitors or, more intriguingly, chronic lymphocytic leukemia-derived epitopes.
Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece.
Anna
A
Vardi
Division of Molecular Oncology and Department of Onco-Hematology, Istituto Scientifico San Raffaele e Fondazione Centro San Raffaele, Milan, Italy.
Andreas
A
Agathangelidis
Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece.
Evangelia
E
Stalika
Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece. Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece.
Maria
M
Karypidou
Immunology and National Tissue Typing Center, General Hospital of Athens "G. Gennimatas," Athens, Greece.
Alexandra
A
Siorenta
Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece.
Achilles
A
Anagnostopoulos
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Richard
R
Rosenquist
Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece.
Anastasia
A
Hadzidimitriou
Division of Molecular Oncology and Department of Onco-Hematology, Istituto Scientifico San Raffaele e Fondazione Centro San Raffaele, Milan, Italy.
Paolo
P
Ghia
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden. lesley.sutton@igp.uu.se.
Lesley-Ann
LA
Sutton
Institute of Applied Biosciences, Center for Research and Technology Hellas, Thessaloniki, Greece. Hematology Department and HCT Unit, G. Papanicolaou Hospital, Thessaloniki, Greece. Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
Kostas
K
Stamatopoulos
D000368:Aged; D000369:Aged, 80 and over; D016022:Case-Control Studies; D060965:Clonal Evolution / Q000235:genetics; D060966:Clonal Selection, Antigen-Mediated / Q000276:immunology*; D030541:Databases, Genetic; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D015321:Gene Rearrangement; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics / Q000276:immunology*; D008875:Middle Aged; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*
D018984:Epitopes, T-Lymphocyte; D016693:Receptors, Antigen, T-Cell, alpha-beta