Evolving T cell responses in murine schistosomiasis. Th2 cells mediate secondary granulomatous hypersensitivity and are regulated by CD8+ T cells in vivo.
The dynamics of T cell maturation and regulation were examined during the granulomatous response to Schistosoma mansoni eggs under conditions of primary (PRIM), secondary vigorous (VIG), and secondary immunomodulated (MOD) immunity. The patterns of VIG and MOD GR (GR) formation were established in naive CBA mice by transfer of lymphoid cells from S. mansoni-infected donors at the VIG and MOD stages of infection. Sequential production of IFN, IL-2, and IL-4 was assessed at the GR and in draining lymph nodes (LN) to determine the participation of Th1 (IFN-producing) and Th2 (IL-4/IL-5-producing) cells. The PRIM GR produced IFN in the growth phase (2-16 days) and IL-4 was detected only after lesions were established (16-24 days). The PRIM LN showed coincident production of IFN, IL-2, and IL-4 on day 4 followed by mainly IL-4 and IL-2 production on day 8, consistent with Th2 differentiation via a Th0 precursor. The VIG GR produced high levels of IL-4 in the growth phase (4-8 days) although IFN remained at modest levels. The VIG LN showed increased cytokine levels consistent with an anamnestic response and again the pattern suggested Th2 differentiation from Th0 cells. The MOD mice had abrogated GR IL-4 levels and arrested Th2 differentiation in LN. In vitro mix studies indicated that the impaired cytokine production was not due to direct suppression. The role of Ts cells was next explored by T cell subset depletion. Pan-T cell depletion of VIG cells profoundly abrogated IL-4 production although CD8+ cell depletion augmented GR area by 70% as well as local and regional IL-4 production by 100 to 150%. Similarly, CD8+ cell depletion of MOD cells augmented GR size and IL-4 production but the response was less than corresponding VIG mice, suggesting that Th activity was reduced in MOD mice. Transfer studies indicated that CD8+ cells inhibited Th2 maturation in LN. Thus, the schistosome egg GR demonstrated a Th1-like pattern in the PRIM response followed by a Th2 pattern in the VIG stage and abrogated Th2 activity in the MOD stage. Finally, the phenomenon of "spontaneous modulation" likely represents the cumulative action of CD8+ cells which steadily erode the Th population.
Chensue
S W
SW
Department of Pathology, Veterans Affairs Medical Center, Ann Arbor, MI 48105.
Warmington
K S
KS
Hershey
S D
SD
Terebuh
P D
PD
Othman
M
M
Kunkel
S L
SL
D000818:Animals; D016827:CD8 Antigens / Q000032:analysis; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D006099:Granuloma / Q000276:immunology; D006967:Hypersensitivity / Q000276:immunology; D007116:Immunization, Passive; D007156:Immunologic Memory; D015847:Interleukin-4 / Q000096:biosynthesis; D008212:Lymphocyte Depletion; D008221:Lymphoid Tissue / Q000166:cytology / Q000276:immunology; D051379:Mice; D008808:Mice, Inbred CBA; D010063:Ovum / Q000276:immunology; D012555:Schistosomiasis mansoni / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D016827:CD8 Antigens; D016207:Cytokines; D015847:Interleukin-4