Evidence for an underlying CD4 helper and CD8 T-cell defect in B-cell-deficient mice: failure to clear persistent virus infection after adoptive immunotherapy with virus-specific memory cells from muMT/muMT mice.
Adoptive transfer of virus-specific memory lymphocytes can be used to identify factors and mechanisms involved in the clearance of persistent virus infections. To analyze the role of B cells in clearing persistent infection with lymphocytic choriomeningitis virus (LCMV), we used B-cell-deficient muMT/muMT (B-/-) mice. B-/- mice controlled an acute LCMV infection with the same kinetics and efficiency as B-cell-competent (B+/+) mice via virus-specific, major histocompatibility complex (MHC) class I-restricted CD8(+) cytotoxic T lymphocytes (CTL). CTL from B-/- and B+/+ mice were equivalent in affinity to known LCMV CTL epitopes and had similar CTL precursor frequencies (pCTL). Adoptive transfer of memory cells from B+/+ mice led to virus clearance from persistently infected B+/+ recipients even after in vitro depletion of B cells, indicating that B cells or immunoglobulins are not required in the transfer population. In contrast, transfer of memory splenocytes from B-/- mice failed to clear virus. Control of virus was restored neither by transferring higher numbers of pCTL nor by supplementing B-/- memory splenocytes with LCMV-immune B cells or immune sera. Instead, B-/- mice were found to have a profound CD4 helper defect. Furthermore, compared to cultured splenocytes from B+/+ mice, those from B-/- mice secreted less gamma interferon (IFN-gamma) and interleukin 2, with differences most pronounced for CD8 T cells. While emphasizing the importance of CD4 T-cell help and IFN-gamma in the control of persistent infections, the CD4 T-helper and CD8 T-cell defects in B-/- mice suggest that B cells contribute to the induction of competent T effector cells.
Homann
D
D
Division of Virology, Department of Neuropharmacology, The Scripps Research Institute, La Jolla, California 92037, USA.
Tishon
A
A
Berger
D P
DP
Weigle
W O
WO
von Herrath
M G
MG
Oldstone
M B
MB
D000818:Animals; D000956:Antigens, Viral; D001402:B-Lymphocytes / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D000939:Epitopes; D007156:Immunologic Memory; D016219:Immunotherapy, Adoptive; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D008211:Lymphocyte Cooperation; D008216:Lymphocytic Choriomeningitis / Q000276:immunology* / Q000628:therapy / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology / Q000302:isolation & purification; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
D000956:Antigens, Viral; D000939:Epitopes; D007376:Interleukin-2; D007371:Interferon-gamma