From: Billi Goldberg <bigoldberg@igc.apc.org>
Subject: Th1 and Th2 Immune Responses
Note: Copyright 1992, Dan R. Greening. Non-commercial reproduction allowed.
Archive-Number: 6425
Organization: unspecified
Date: Sat, 7 Nov 92 08:08:55 PST

                     TH1 AND TH2 IMMUNE RESPONSES

The following three studies are very interesting and might be very 
important. Evidence is growing that the Th1 (CMI) and Th2 (antibody) 
response exists in humans and is an integral part of the human immune 
response.

Stout et al. shows that activation of the Th2 response might suppress 
the activation of Th1 in macrophages. This is extremely important since 
macrophages are critical cells in control of AIDS pathogens which are 
obligate intracellular in nature. Therefore, excessive activation of Th2 
(by hypergammaglobulinemia) or by chronic diseases such as Leishmania 
and syphilis may result in early clearance of localized infection via 
DTH-macrophage activation, transient concomitant immunity during acute 
infection, development of macrophage suppression through Th2 responses 
and then chronic infection.

Simon et al. reports on the suppression of Th1 responses by UVB 
resulting in clonal anergy of antigen-specific T cells during antigen 
presentation of cutaneous pathogens in the skin.  These suppressive 
effects are primarily in the epidermal Langerhans cells which are unable 
to transduce the co-stimulatory signal required for T cell activation. 
Whether are not UVB effects other lymphoid tissue APCs such as dendritic 
cells has not been determined. But UVB does not result in suppression of 
Th2 responses because a co-stimulatory signal is not required. UVB 
appears to act in same way on LC as HIV infection acts on LC/DC. HIV 
infection of LC/DC appears to result in clonal anergy or clonal deletion 
of antigen-specific T cells when activated by the Th1 or cell mediated 
immune response.

Abehsira-Amar et al. believes that lymphokine production of IL-2 and  
interferon-gamma is required for activation of Th1 while IL-2 and IL-4 
are required for activation of Th2. IL-4 seems to be the critical 
lymphokine in determine whether Th1 or Th2 result from the initial Th0 
state. IL-5 and IL-10 also appear to play important roles in activation 
of Th2 responses.
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Stout RD; Bottomly K.                                                 
Antigen-specific activation of effector macrophages by IFN-gamma 
producing (TH1) T cell clones. Failure of IL-4-producing (TH2) T cell 
clones to activate effector function in macrophages.
Journal of Immunology, 1989 Feb 1, 142(3):760-5.       

Abstract: IFN-gamma-producing (TH1) and IL-4-producing (TH2) clones were 
assayed for their ability to directly induce cytostatic activity in   
macrophages generated from splenic myeloid precursors (M phi-c). In the
presence, but not in the absence, of antigen, TH1 clones activated the M
phi-c to inhibit the growth of P815 tumor cells in vitro. TH2 clones 
were not able to activate such effector activity in the M phi-c. The M 
phi-c did effectively present Ag to the TH2 clones as evidenced by the 
proliferation of TH2 cells cultured with Ag in the presence, but not in 
the absence, of M phi-c. Therefore, although both TH1 and TH2 were 
activated by cognate interaction with antigen presenting M phi-c, only 
TH1:M phi-c interactions displayed reciprocity resulting in activation 
of the M phi-c. TH1-derived lymphokines or rIFN-gamma, in the presence 
of LPS, could activate proteose-peptone elicited M phi, resident 
peritoneal M phi, and M phi-c whereas neither TH2-derived lymphokines 
nor rIL4 could induce detectable activity in any of the 3 M phi 
populations. IFN-gamma, in the absence of LPS, could activate the 
elicited M phi and to a lesser and more variable degree, the resident M 
phi Only the M phi-c consistently required both IFN-gamma and LPS for 
induction of cytostatic activity. Since M phi-c consistently required at 
least two signals for activation, the ability of TH1-derived lymphokines 
to synergize with TH2 cells in M phi activation was examined. TH2 could 
activate the Ag-presenting M phi-c in the presence of IFN-gamma. The 
ability of added IFN-gamma to synergize with TH2 indicates that the 
cognate interaction between TH2 and antigen presenting M phi-c does 
result in delivery of at least one of the signal required for M phi
activation.
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Simon JC; Krutmann J; Elmets CA; Bergstresser PR; Cruz PD Jr. 
Ultraviolet B-irradiated antigen-presenting cells display altered 
accessory signaling for T-cell activation: relevance to immune responses 
initiated in skin. 
Journal of Investigative Dermatology, 1992 Jun, 98(6 Suppl):66S-69S. 

Abstract: A principal mechanism by which ultraviolet (UV) B radiation 
exerts its selective and antigen-specific suppressive influence on 
immune responses is through its effects on the capacity of antigen-
presenting cells (APC) in skin, primarily Langerhans cells (LC), to 
differentially activate T-cell subsets. Recent evidence has indicated 
that LC, following UVB radiation, lose the capacity to stimulate 
proliferation of CD4+ Th1, but not of Th2, clones. Additional work has 
shown this acquired unresponsiveness of Th1 cells to represent a long-
lasting form of clonal anergy that results from a block in their ability 
to produce IL-2. Although not completely delineated, these defects 
appear to be the result of preserved delivery of the primary signal 
transduced by interaction of the MHC/antigen complex on APC with the T-
cell receptor complex, in the absence of a viable second signal normally 
delivered by interaction of a co-stimulatory factor from APC with its 
appropriate ligand on the T cells. These findings support the notion 
that the outcome of certain immune responses depends greatly upon 
conditions that are brought to bear on APC and T cells during the time 
of antigen presentation. 
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Abehsira-Amar O; Gibert M; Joliy M; Theze J; Jankovic DL. 
IL-4 plays a dominant role in the differential development of Tho into 
Th1 and Th2 cells. 
Journal of Immunology, 1992 Jun 15, 148(12):3820-9. 

Abstract: We have analyzed the evolution of the pattern of lymphokine 
secretion by Th cell lines specific for either the synthetic terpolymer 
Glu60Ala30Tyr10 (GAT) or killed bacillus Calmette Guerin. When cultured 
in the presence of exogenous rIL-2 as a growth factor, GAT-specific Th 
cell lines secreted mainly IL-4, whereas bacillus Calmette Guerin-
specific lines produced predominantly IL-2. However, culturing in the 
presence of rIL-4 or of anti-IL-4 mAb and rIL-2 led to the establishment 
of Th2-like and Th1-like lines, respectively, regardless of their Ag 
specificity. Inasmuch as we show that the proliferative response of 
mature Th1 and Th2 cells was identical in the presence of IL-4, these 
results indicate that IL-4 influences the development of Th cell 
subsets. To understand the mode of IL-4 action, we isolated immature 
GAT-specific Tho clones able to secrete IL-2 and IL-4. Two types of Tho 
cells were isolated: ThoA cells that secreted IL-2 and IL-4, but not 
IFN-gamma, and ThoB cells that secreted IL-2, IL-4, and IFN-gamma. We 
show for the first time that such cells are indeed Th precursors able to 
differentiate into Th1 or Th2 cells. We demonstrate that IL-4 positively 
and negatively controls the differentiation of Tho cells into Th2 and 
Th1 cells, respectively. When cultured in rIL-4, Tho cells stop 
secreting IL-2 and IFN-gamma, but maintain IL-4 secretion. Moreover, 
endogenous IL-4 produced by Tho cells has similar effects: when cultured 
in rIL-2 alone, Tho cells either keep their immature phenotype or become 
Th2 cells, but do not become Th1 cells. In contrast, neutralization of 
secreted IL-4 completely prevents the differentiation of Tho into Th2 
cells, but permits the development of Th1 cells. The presence of 
exogenous IFN-gamma does not affect the development of Tho into Th1 and 
Th2 cells, because it does not modify either mode of IL-4 action. 
However, it influences the ratio between the two types of Tho cells: 
when IL-4 is neutralized, added IFN-gamma can induce IFN-gamma secretion 
by ThoA cells and thereby facilitate their passage into ThoB cells. 
Taken together, our results demonstrate that IL-4, in addition to 
mediating T cell growth, is a principal factor that controls 
the differential development of Tho cells into Th1 and Th2 cells. 
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