Oligoclonal T cell receptor gene
rearrangements in blood lymphocytes of
patients with acute Epstein-Barr virus-induced
J G Strickler, … , R D Brunning, L M Weiss
J Clin Invest.
Gene rearrangement studies were performed on blood lymphocytes from eight patients with
acute Epstein-Barr virus-induced infectious mononucleosis. The diagnosis in each case
was based on characteristic clinical, hematologic, and serologic findings. The blood
lymphocytes in each patient consisted predominantly of CD8+ T cells. EBV DNA was
detected in seven patients by Southern blot analysis (EBV Bam HI W probe, Bam HI). A
germline configuration was found for the immunoglobulin heavy and light chain genes (JH
probe, Bam HI and Eco RI; C kappa probe, Bam HI; and C lambda probe, Eco RI). T cell
receptor gene rearrangements were detected with J gamma and J beta 1 + 2 probes. Using
a J gamma probe with two different restriction enzymes (Bgl II and Eco RI), the blood from
each patient showed several bands corresponding to the polyclonal pattern previously
described in the blood of normal individuals. Using J beta 1 + 2 probes with two different
restriction enzymes (Bgl II and Bam HI), each case showed from 3 to about 12 extragermline
bands of varying intensity and in different locations from case to case. In addition, each case
showed relative deletion of the J beta 1 germline band. This oligoclonal pattern of T cell
receptor gene rearrangements has not been previously reported in benign or malignant T
Cell Receptor Gene
Rearrangements in Blood Lymphocytes
Patients with Acute Epstein-Barr
John G. Strickler,* Lucile A.
Movahed,lKazimiera J.Gajl-Peczalska,*CharlesA.Horwitz,* Richard D. Brunning,* and LawrenceM.Weissil
*Departments ofPathology, University ofMinnesota Hospital, Minneapolis, Minnesota 55455; tMetropolitan-MountSinai
MedicalCenter, Minneapolis, Minnesota 55404; §Stanford University Medical Center, Stanford, California 94305; andI1CityofHope Medical Center, Duarte, California 91010-0269
Gene rearrangement studies were performed on blood lympho-cytes from
eightpatients with acute Epstein-Barr virus-in-duced infectious mononucleosis. The diagnosis in each case wasbased on characteristic clinical,
serglogicfindings. The blood
lymphocytesin each patient
of CD8+Tcells. EBV DNA was detected in seven
patientsby Southern blot
analysis(EBV Bam HI W probe, Bam HI).Agermline
configurationwas found for the immuno-globulin heavy and light chain genes (JH probe, BamHIand Eco RI;
C,probe, Bam HI; and
CAprobe, Eco RI). T cell receptor gene rearrangements were detected with
J,01+2probes. Using a
J,probe with two
differentrestriction enzymes (Bgl II and Eco
RI),the blood from each patient showed sev-eralbands
correspondingtothepolyclonal pattern previously described in the blood of normal individuals.
different restrictionenzymes (Bgl II and Bam HI), each case showed from 3 to about 12 extragermline bands ofvarying intensity and in
differentlocationsfromcase to case. In addition, each case showed relative deletion of the
oligoclonalpattern ofTcell receptor gene rearrangements has not been previously reported in benign or malignant T cell populations. (J.
Clin.Invest. 1990. 86:1358-1363). Key words: Southern blot .
clonality-CD8+ Tcells .
Withinthe last five years, the
TCR'gene has been usedas amarker of
clonalityin T cell
Generally,the presence ofone or two
AddressreprintrequeststoDr. LawrenceWeiss, 2241 Anatomic
Pa-thology, City of Hope National Medical Center, 1500 East Duarte
Road,Duarte, CA 91010-0269.
Receivedfor publication 20 April 1990 and in revisedform 15 June
1. Abbreviations usedin this paper: EBNA, EBV-associated nuclear antigens; EBV-IM, EBV-induced infectious mononucleosis; TCR,T
cellreceptor;VCA, EBV-specificviralcapsid antigens.
effective indicator ofa
while benign T cell populations have usually demonstrated a
germline configuration,often with relativeorabsolute deletion
031locus. There are
thisrule; for example, clonal
populationshave been ob-served intwo
dermatologic disorders, lymphomatoid
varioliformisacuta, that mayrepresent low-grade T cell
malignanciesrather than truly
AcuteEBV-IM is usually considered to be a benign, self-limited
diseasecaused by a primary Epstein-Barr virus infec-tion. It
oropharyngeal epithelium (13).The virus reaches Wal-deyer's
ringby way of the
epithelium,where infection and
lymphocytes proliferate locallyand may
infection,but the number
of EBV-infectedB cellsis
usuallyless than 0.05%
blood mononuclear cells
(16).Most of the
lympho-cytes in the blood
which are thoughttobe
primarily responsible for limitingand
patientshavebeen showntodelay outgrowth of autologous
lymphocytes (17)and to inhibit
fetal lymphocytes (18).
thisreport, we have
possibilitythat clonal TCR gene rearrangements may be
immunogenotypic studiesof blood
Moreover, we report that these T cells have a
oligo-clonal TCR genotype, apattern of
clonalitythat hasnot pre-viously been described in
Caseselection.Theinvestigationwasperformed after approval bythe
Committeeonthe UseofHumanSubjectsin Researchatthe Univer-sity of Minnesota.Eightpatientswho hadcharacteristicclinical,
hema-tologic,andserologicfindings ofacuteEBV-IMwerechosenfor study.
Allpatientsweremale students(ages 18-22)attheUniversity of Min-nesotawith clinical symptoms typical ofacute EBV-IM, including fever, sorethroat, andlymphadenopathy. Thediagnosisin each
pa-tient was confirmed by standard serologic methods (see Results) (20-23).Noneofthepatientshadahistory of inheritedoracquired immunodeficiency.
©TheAmericanSocietyfor ClinicalInvestigation,Inc. 002
TableI. PertinentLaboratoryDatafrom EightPatientswith AcuteEpstein-Barr Virus-inducedInfectiousMononucleosis
in differential Heterophil
Case WBC x109/L (atypicals)* (horsecells)t VCA-IgM VCA-IgG EBNA
1 7.7 88(85) 1:448 .1:160 1:80 <1:2 2 11.0 52(45) 1:4336 >1:160 1:160-1:320 <1:2 3 16.6 74(38) 1:224 1:80-1:160 1:320 <1:2 4 23.0 83 (36) 1:224 1:10-1:20 1:640 <1:2 5 8.5 78(55) 1:224 1:160-1:320 1:320 <1:2 6 24.5 78(65) 1:224 1:160 1:320-1:640 <1.2 7 6.3 54 (18) 1:448 .1:160 1:160 <1:2 8 12.4 52(17) 1:448 1:160 1:640 <1:2
* Number in parentheses referstothe numberofatypical
100white blood cells. $ Monospot tests (Ortho Diagnostic)were
alsopositive in eachcase.
Immunophenotypestudies. The blood lymphocytes fromeach case
were evaluatedusing immunologic marker studies and flow cytometry, aspreviously described(24). A panel ofB-and
T-lymphocyte-asso-ciated monoclonalantibodies wasapplied, includingthe pan-B cell antibody B43 (CD19; Fatih Uckun, University ofMinnesota), the pan-T antibodies 13B3(CD2;DanVallera,UniversityofMinnesota),
T3(CD3;CoulterImmunology,Hialeah,FL), TIOI (CD5;Dan
Val-lera), and G3.7(CD7;DanVallera), the helperTcellantibody anti-Leu3(CD4; BectonDickinson, MountainView,CA), and the
Immunogenotype studies. DNAfrom blood lymphocytes, which had been isolated usingFicoll-Hypaque density gradient centrifuga-tion,wasextracted andpurified accordingtostandardprocedures (25). 10 ,ug ofDNAwasdigested withan appropriate restriction enzyme, and theresultingfragments wereseparated by gel electrophoresis in 0.8% agarosegel. Separated DNA fragments werethen transferred from the gels onto activated nylonmembranes(Genatran-45; Plasco, Woburn, MA) by thetransfer method of Southern(26).Membranes werethenhybridized with DNA probefragments that had been
32P-la-beledby the randomoligonucleotidepriming technique(27). Details ofthemethodsof hybridization and autoradiography havebeen pre-viously described (25).DNAprobefragments usedincluded the join-ing region ofthe Ig heavy chain gene, the constant regions ofthe kappa
and lambdaIglight chain genes (25), the joining region ofthegamma TCR gene(11),andthejoining regions of thebeta TCRgene(12).
Restriction enzymes were purchased from New England Biolabs, Beverly, MA.
DetectionofEpstein-Barr virus. Southern blothybridization stud-ies wereperformedas described elsewhere, (25, 26) using 10 sg of purifiedDNAdigested byBamHI.Theresulting fragmentswere
elec-trophoreticallyfractionatedaccordingtosize and transferredonto
ac-tivatednylon membranes.Hybridizationwasperformed withtwo
sep-arateEBVprobefragmentsthat had been32P-labeledbythe random oligonucleotide primingtechnique (27).Oneprobeconsisted ofaBam
HI Wfragment of EBVDNA(28), and the otherprobewas a5.2-kb
Bam HI-Eco RIrestrictionfragmentcontainingthe500bptandem terminal repeated sequence of theEBVgenome(29).
absolute white blood cellcount wasnormal in three
fivecases. All cases
50% lymphocytesand atleast 10%
atypical forms inthe
heterophiltiter was 1:224 or greater in all
ineach case. EBV
1:2) anti-EBNA titers.
summarizedin Table II.
cells, withB cells comprising 2% or less
Case Case2 Case3 Case4 Case5 Case6 Case7 Case8
CD19 2 7 2 1 1 1 1 2
CD2 96 90 96 83 94 98 92 92
CD3 89 78 90 77 70 94 79 80
CD5 85 82 91 72 58 88 76 71
CD7 35 78 94 55 61 ND 29 61
CD4 13 32 10 15 12 8 24 22
CD8 76 37 83 57 54 75 65 50
CD4:CD8 ratio 0.17 0.86 0.12 0.26 0.22 0.11 0.37 0.44
probewith two separate restriction enzymes
(BglII and Eco
RI),the blood from each
patientshowed several bands
previouslydescribed in the blood of normal individuals
HI),eachcaseshowedfrom 3to -12 bands of
inten-sityand in different locations from case to case
addition,eachcaseshowed relative deletion of the
germlineband. For each case, an identical
oligoclonalrearrangement pattern wasobtained after
hybridizationof blots obtained
digestsfor each of the
digestionof DNA contributed to the
8This pattern of
oligoclonalrearrangements has not been
ob-re1.Portion ofaSouthern blot
autoradiogram(prolongedexpo- served inour
analysisfor EBV nucleic acids
usingthe EBVBarn and
HIWprobeand Barn HI restrictionenzyme.Faint bandsat3 kbare seenin all lanes except lane2,
indicatingalow numberofcopiesof EBVgenomesin theperipheralblood
lymphocytesofpatients 1 and 3-8.
2. No aberrant
cases 1 and 7 was somewhat lower than
higherCD4:CD8 ratio andmoreBcells than other
EBV DNAwasdetected inseven cases
usingthe EBV Bam HI W
(Fig. 1).The Southern blot
autoradiogramfrom these seven
patientsrevealedfaint bands after
indicatinga very low copy numberofEBV genomes. There
immunologicdif-ferences between the seven
positivecases and the
negativecase.EBV genomecouldnotbedetected in blood
eight patientsin Southern blot
The results of the
summa-rized in Table III. A
configurationwas found for
However,rearrangements of the beta and
gammaTCR genesweredetected in each
Ourstudy of theimmunophenotypeandEBV statusof blood
lymphocytes in acute EBV-IM patients agrees with
observa-tions in other studies. Previous studies have shown that CD8+
Tlymphocytesarethepredominantcell typein the blood of
EBV-IMpatients (1 9),and theseobservationsareconfirmedin
ourseries. Although previous reports have shown that EBV-infected Blymphocytesarefound in the blood in low numbers
(16), EBVgenomewasdetected in the bloodofsevenofeight
patients,usingSouthern blotanalysiswith the EBV BamHI W
probe.Since theEBVterminalrepeatedsequenceprobeis less sensitive than the Bam HIWprobe,it isnotsurprisingthatwe
were notable to use thisprobe to assess theclonality of the
EBV-infectedlymphocytes, duetoinsufficientcopiesof EBV genome in the specimens. Polymerase chain reaction
tech-niqueswould mostlikelydemonstrate EBVgenomein blood
lymphocytesfrom all EBV-IMpatients,butthistechniquealso
could potentiallydetect EBV inthebloodofanypatients
The polyclonal pattern ofgamma TCR rearrangements
seeninourseries has beenpreviouslydescribed in the blood of normal individuals (30). The gamma TCR gene has only a
small numberof variable region segments, so that there is a
analysis ofpolyclonal T cell populations in normal patients
mayyield asetofnongermlinebandscorresponding toall of
thepotential rearrangementsof thisgene.
CaweI Caw 2 Caw 3 Cawe4 Caw 5 Cawe6 Cawe7 Caw 8
JH(Bam HI) G G G G G G G G
JH(Eco RI) G G G G G G G G
',C,,(BamHI) G G G G G G G G
C,\(EcoRI) G G G G G G G G
(BgI1II)PR PR PR PR PR PR PR PR
Jy(Eco RI) PR PR PR PR PR PR PR PR
J#1+2(BgI II) OR OR OR OR OR OR OR OR
J,012(Barn HI) OR OR OR OR OR OR OR OR
Figure 2.Composite autoradiogram, derived fromtwoseparate gels,
showinganalysis of the beta TCRgeneusinga
Jo6+2probeandBgl II restrictionenzyme. Thebackgroundappearshighbecause of the
pro-longedtime ofexposure(9d). All lanes are loadedwiththe same amountofDNA.Crepresents a controlperipheralblood specimen
fromanormal individual. Germlinebands aredesignatedby the arrows. Alleightcasesshowfrom 3to 12extragermlinebandsof varying sizeandintensity. Inaddition, theJo1germline (at the upper
arrow) is diminished in intensity comparedtothelowertwo
germlinebands. Patient 1 lacks the lower
J62germline band dueto
the absenceofapolymorphism that ispresentinthe DNAfromthe
ofbeta TCR gene rearrangements
foundin the blood
patientsin our series has not been
inthe blood or
pa-tients with other benignor
large majority of malignantTcell
populationsare thought to bemonoclonal,
singlecell that has already
of itsTCR genes, each T cell
ofone or two nongermline rear-rangement bands on
analysis(because either or
both oftwoalleles may undergo rearrangement) (1-9). Three rearrangement bands have been reported to occur in several
Southern blot analyses oftwo
lym-phoproliferative disorders, lymphomatoid papulosisand
disease) (10-12). Althoughthe appearance of three bands may beduetothe presence
ofmorethanoneclone of Tcells, other explanations include abnormal rearrangements, chromosomal
somatic mutationof DNA of a
rearranged gene in some
oftheclonal cells in a mono-clonal
population.Incontrast, mostbenign T cellpopulations are
presumablypolyclonal, with each clone of T cells havinga
uniquebetaTCR rearrangement. Since
pop-ulations consist ofenormous numbers of T cell
comprises onlyavery small
is large enoughtobe
detectable by Southernblot
analysis. However, relativeor
ab-solute deletion ofthe
Jo1 germline bandis oftenseenbecause theTcellsare
Incontrast to the patterns discussed above, our Southern blot
analysis ofthe blood
patientsrevealed from 3 toabout 12 beta TCR
ineverycase. This most
likelyindicates that several clones of T cells are present, but many less than
inthe polyclonal populations of T cells present in most benign disorders. The rearrangement bands were
ofvarying intensity and in different locations from case
foreach case. The
relativedeletion of the
Jo1germline band also provides
indirect evidencethat the beta TCR genes in these T
immunoglobulingene rearrangements has been reported in
from AIDS patients(35). However,
germlinepattern was seen on
analysis ofthe beta TCR gene in these cases.
patientsareknown to have a
lymphoma, while individuals
who have had acute EBV-IM have no known
lymphoma.Recently, one or two clonal
lymphocytic leukemia and
performing Southern blotting studies
Ithas been proposed that the T lymphocytes in the blood
patients ofacute EBV-IM are
patient. Since there isa
of correlationbetween the appearance
of humoral immunity
from EBV-IM, attentionhas
prime mediator ofrecovery
outgrowth of autologous EBV-infectedB
inhibit outgrowth of EBV-transformed
(18). Outgrowth inhibitioncan be demonstrated
isgreatest when the
rear-rangements will not be
EBV-associatedacuteEBV-IM, but may
alsobe encountered in otheracute
oligoclonalTCR gene rearrangements
-j, .,W, 1:1. --ts"
the evaluation of the blood of known or suspected lymphoma patients by gene rearrangement studies. The presence of extra-germline bands alone should not be used to constitute
evi-dence ofmalignantTcellclone if thepatientissuffering from anintercurrent illness that may be viral in nature. Although a unique pattern of 3 to 12bands wasobservedinall eight cases reported here, it is likely that, at some point in each of these patients' courses, onlyone or twobandsmayhavebeen detect-able.
The authors thank Dr. Michael L. Cleary, in whose laboratory the gene rearrangement studies were performed. The blood samples were
col-lectedby JanetSchultz, M.T. Technical assistance for the
immuno-phenotyping studies was provided by Mary Jane Kraft-Weisjahn, Karen Harris, Kay Kruel, Kim Schaper, Cindy Stanaway, Cathy
Carollo-Neumann,andDianeJohnson. Carol Ghandour provided
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