NetNews Usenet Archive 1992 #26/NN_1992_26.iso/spool/sci/med/aids/1978

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From: Billi Goldberg <[e-mail]>
Subject: Th1 and Th2 Immune Responses
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Note: Copyright 1992, Dan R. Greening. Non-commercial reproduction allowed.
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                     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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