The Compendium January 1997 Small Animal

PERSPECTIVES IN VETERINARY MEDICINE V

Advances in Immunology:
Role of T-Helper Lymphocyte Subsets
Keith A. Hnilica, DVM
Donna W. Angarano, DVM
Diplomate, ACVD
College of Veterinary Medicine
Auburn University
Auburn, Alabama
cells, T-suppressor cells, and
cytotoxic T cells. In 1986, it
was discovered that T-helper
cells could be further subdivid-
ed into two distinct subsets:
TH1 and TH2 cells.1 These func-
tionally polar subsets are princi-
pal regulators of the immune
system—they direct the im-
mune response.1–3
didiasis, and leishmaniasis) ini-
tiate a TH1 response, but if the
infection is not completely
cleared, the immune reaction
may switch to the T H 2 re-
sponse. 5–8 When the T H 2 re-
sponse becomes the predomi-
nant reaction in an infection,
widespread tissue involvement
results and severe systemic dis-
cent studies have implicated TH2
cells in the development of
atherosclerosis.22
Factors for Subset
Proliferation
Multiple factors (e.g., genet-
ics, antigen dose and structure,
and antigen-presenting cells)
influence the stimulation of

W
ith the advances in
medical technolo-
gy, practitioners
often find themselves practicing
medicine on the cellular and
molecular levels—especially in
immunology. AIDS has been a
major driving force in immunol-
ogy; as a result, many facets of
the immune system have been
better characterized. T lympho-
The two fundamental types
of immune response are innate
and acquired immunity. Innate
immunity involves phagocytes
(macrophages and neutrophils),
which recognize foreign anti-
gens nonspecifically. Innate im-
munity is the initial immune re-
sponse and requires no previous
antigen exposure to be activat-
ed. Acquired immunity is an
ease often follows.5–7 TH1 lym- specific T-helper cell subsets1–4
phocytes have been implicated (Figure 1). Antigenic factors are
in various pathologic processes, among the most important.3,4
including autoimmune diseases The structure of the antigen, the
(e.g., multiple sclerosis, insulin- route of presentation, and the
dependent diabetes mellitus, dose are all critical in T-cell pro-
and rheumatoid arthritis), graft motion, but the role of each
■ T-helper lymphocytes can be divided into two
functionally distinct groups: T-helper 1 and T-
KEY POINTS

cytes are only one element of
the immune system, but they
play a significant role in dis-
ease.
The immune system is so
complex that it is often an over-
whelming task to keep abreast
of changes. This column re-
views the recent developments
in T-cell function, with special
attention to the T-helper cell
subsets (T-helper 1 [TH1] and
2 [TH2] cells) and their role in
normal immune responses as
well as aberrant T-lymphocyte
function.
T-Helper
Lymphocyte Subsets
T lymphocytes are classified
into functional groups: T-helper
antigen-specific response that
needs previous exposure to the
foreign antigen. In general, TH1
cells stimulate innate and cell-
mediated immunity, and TH2
cells stimulate humoral immu-
nity, eosinophils, and mast
cells.1–3 When stimulated, each
T-helper cell subset inhibits the
development of the alternative
subset; thus, diseases typically
involve either a TH1 or a TH2 re-
sponse.1,2,4
The TH1 response is most ef-
ficient at defending the host
from infection. Bacteria and
viruses usually initiate a TH1 re-
sponse, which promotes an im-
mune reaction that resolves the
infection.2,3 Some infectious dis-
eases (e.g., AIDS, leprosy, can-
helper 2 lymphocytes.
■ T-helper 1 lymphocytes stimulate cell-mediated
and innate immunity, whereas T-helper 2 lym-
phocytes stimulate humoral immunity.
■ It is now possible to develop novel therapies
that alter T-helper lymphocyte subset response.
rejection, inflammatory bowel antigenic factor remains poorly
disease, and psoriasis.9–16 characterized.2–4 Antigen-pre-
The TH2 response may be a senting cells survey the local
modification made by the host’s tissue environment and process
immune system to prevent dam- antigens for presentation to the
aging immune reactions (from appropriate component of the
the TH1 response) in chronic immune system. Specific anti-
disease. TH2 lymphocytes are gen-presenting cells process
the primary effector cells in aller- and present antigens differently.
gy, parasitic infection, lupus, TH1 cells are preferentially acti-
shingles, and AIDS.5,8–11,17–21 In vated by macrophages, and TH2
HIV-positive individuals, the TH2 cells are stimulated by tissue-
lymphocyte response leads to a specific dendritic cells.
more rapid onset of AIDS.5 Re- Atopic dermatitis serves as a
The Compendium January 1997
T-helper 1 T-helper
precursor
Figure 1—The differentiation of T-helper lymphocytes depends on multiple factors, including genetics, antigen characteristics, and mi-
croenvironment. IL = interleukin.
TABLE ONE
T-Helper 1 Lymphocyte Cytokines
and Their Functions
Cytokine Immunologic Effect
Interleukin-2 Activates TH1 lymphocytes
Stimulates cell-mediated immunity
Induces interferon-γ production
Interferon-γ Activates TH1 lymphocytes
Inhibits TH2 lymphocytes
Activates mononuclear cells
Increases phagocytosis and killing
Upregulates cell surface receptors
Tumor necrosis Activates neutrophils
factor-β Upregulates adhesion molecules
and cytokine production
good model for the specific ac- gerated response was attribut-
tivation of TH2 cells. Allergy is ed to genes that regulate TH2
an abnormal immunologic con- promotion.4,17–21
dition that is closely linked to In allergic individuals, the
the genes that regulate inter- Langerhans’ cells sample the
leukin (IL)-4 production, which antigenic environment in the
leads to a TH2 response.18,20 In epidermis. 20 Any exogenous
one study, allergic and normal antigen is engulfed and pro-
individuals responded to aller- cessed within the Birbeck gran-
gens through a similar im- ules. The Langerhans’ cells pre-
munologic pathway; however, ferentially present the antigen to
the responses of the allergic in- TH2 cells, which are then acti-
dividuals were exaggerated.20 vated through cell surface–recep-
The combination of normal tor interactions and cytokine se-
antigen processing and exag- cretions.5,20 IL-4 is one of the
Genetics
Antigen characteristics (parasites)
T-helper 2 Antigen dose, route
Antigen-presenting cells (Langerhans’
cells)
Cytokines (IL-4, IL-5, IL-10)
most important promoters of
TH2 cell differentiation and pro-
liferation.20 Activation of TH2
cells is affected by additional
factors, including chemokines
and local hormones (e.g., glu-
cocorticoids, calcitriol, and pro-
gesterone).5,17,18 In vitro studies
in mice suggest that glucocorti-
coids may promote TH2 cell dif-
ferentiation and proliferation.17
Atopic dermatitis is frequently
treated with steroids; however,
if glucocorticoids promote the
response that they are being
used to diminish, then such
treatment could be detrimental.
Immunology and
Disease Models
The function of each T-helper
cell subset is related to its
unique cytokine profile. TH1 cells
synthesize and secrete IL-2, in-
terferon-γ, and tumor necrosis
factor-β (Table One). TH2 cells
produce IL-4, IL-5, IL-10, and
IL-131,2,4 (Table Two). Individual
cytokines have many functions.
In general, the cytokines secret-
ed by TH1 cells stimulate cell-
mediated reactions, monocytes,
and macrophages. TH2 cell cy-
tokines stimulate a humoral im-
mune response, eosinophils,
and mast cells.1–4,17–19
Infectious Diseases
Studies of leishmaniasis,
candidiasis, human leprosy,
Small Animal
and AIDS have produced much
of the current information about
TH1 cells and subset switch-
ing.5–7 Each disease initially pro-
motes an active cellular im-
mune response that attempts to
kill and remove the causative
organism. This phase of the im-
mune response is promoted by
TH1 cells and their cytokines.5–7
At this stage, the disease is lo-
calized and the patient is in rela-
tive good health.
When disease becomes
chronic, the immune response
switches from a TH1 to a TH2
response. This change leads to
stimulation of eosinophils, mast
cells, and B lymphocytes, which
limits the infection but is less ef-
fective than a TH1 response. Clin-
ically, the disease tends to become
systemic. In AIDS and leproma-
tous leprosy, the TH2 response
is associated with widespread
disease and rapid patient de-
compensation. 5,6 Thus, T H 1
cells promote a protective im-
mune reaction, whereas TH2
cells permit disease dissemina-
tion.
Allergy
Atopic dermatitis is a com-
mon disease in veterinary
medicine. Human studies have
shown that the TH2 response
plays a central role in the
pathophysiology of allergy. In
the skin, Langerhans’ cells
Small Animal
Figure 2—The allergy loop, showing the interaction of the
Langerhans’ cells, T-helper lymphocytes (TH2), B lymphocytes
(B ), mast cells, and IgE. IL = interleukin. (From Hnilica KA: The
TH2 immune response and the pathogenesis of allergy. Vet Allergy
Clin Immunol 4(4):129, 1996. Reproduced with permission.)
sample the environment and
preferentially activate T H 2
cells.17–20 The TH2 cells secrete
cytokines that activate B lym-
phocytes, eosinophils, and
mast cells.4,17–20 B lymphocytes
produce IgE, which is incorpo-
rated onto the surface of the
Langerhans’ cells and mast
cells. This allows specific sam-
pling of epidermal antigens by
Langerhans’ cells and antigen-
specific stimulation of mast
cells.4,17–20 Mast cells can also
process and present antigens
to TH2 cells and can produce
IL-4.4,20 An allergy loop (Figure
2) that leads to a self-promot-
ing and self-perpetuating cycle
of inflammation in allergic indi-
viduals is formed. In addition,
the inflammatory reaction in
the epidermis and resulting
keratinocyte damage lead to
the production and release of
additional compounds that
promote the allergic reaction
(Figure 3).
The Compendium January 1997
toantibodies causes such prob- cally suppress T lymphocytes
lems as glomerulonephritis and by using compounds that target
vasculitis.11 If the T-helper cell these cells. Several clinical trials
subset can be switched to the in humans have had favorable
alternative subset, these dis- results.18,20
eases may be arrested. Atopic dermatitis can often be
improved with the use of allergen-
Therapeutic Modifiers specific immunotherapy. During
TH2 A key aspect of T-helper cell hyposensitization treatment,
response is the inhibitory effect IL-4 levels decrease, thus indi-
of one subset on the other sub- cating suppression of the TH2
set. This mutual inhibition of- immune response.20 This effect may
fers hope that practical thera- be caused by antigen-specific
pies can be designed to modify tolerance, T-cell suppression,
the immune response by or T-helper subset switching
changing the T-helper cell sub- from TH2 to TH1 cells.18,20,21 In
set. Some treatments specifi- another study, allergic individu-
TABLE TWO
T-Helper 2 Lymphocyte Cytokines
and Their Functions
Cytokine Immunologic Effect
Autoimmunity Interleukin-4 Activates TH2 lymphocytes
Most autoimmune diseases Activates B lymphocytes
are promoted and perpetuated Initiates immunoglobulin class
by TH1 cells.9,10 Studies of hu- switching (IgE)
man diseases using animal Promotes chemotaxis of
models have shown that the eosinophils
autoimmune diseases multiple Upregulates ICAM-1 and VCAM-1
sclerosis, insulin-dependent Increases mast cell growth factor
diabetes mellitus, and rheum-
atoid arthritis are closely asso-
ciated with a T H 1 immune Interleukin-5 Promotes chemotaxis and
response.9,10,12 The TH1 cells stim- activation of eosinophils
ulate a cell-mediated reaction di- Activates B lymphocytes
rected at the autoantigen.9,10,12,13 Stimulates IgA synthesis
The resulting inflammation
causes damage to the targeted
Interleukin-10 Activates TH2 lymphocytes
molecule and surrounding tis-
Activates B lymphocytes
sue and the clinical manifesta-
Initiates mast cell proliferation
tion of disease—neuropathy,
Inhibits macrophages
diabetes, or arthritis, respec-
tively.9,10,12
Other diseases, such as lu- Interleukin-13 Activates TH2 lymphocytes
pus, are promoted by the TH2 Initiates immunoglobulin class
immune response. TH2 cells switching (IgE)
stimulate autoantibody produc-
tion, which leads to an exagger- ICAM = intercellular adhesion molecules, VCAM =
ated humoral response.11 The vascular cell adhesion molecules.
large amount of circulating au-
The Compendium January 1997 Small Animal

TABLE THREE
Immune Response Modifiers
Immune Modulators Immunologic Effect Possible Application

Specific
Interferon-γ Stimulates innate immunity; promotes Atopic dermatitis; infectious disease;
the TH1 response; inhibits the TH2 adjuvant therapy for neoplasia
response

Interleukin-12 Promotes the TH1 response; inhibits Convert immune response from
the TH2 response TH2 to TH1; chronic infections

Cyclosporine Inhibits lymphocyte function; Atopic dermatitis; organ transplants;

suppresses cytokine production keratoconjunctivitis sicca

Staphylococcal vaccine Stimulates TH1 cytokine production; Recurrent idiopathic pyoderma;

stimulates innate immunity staphylococcal hypersensitivity

Nonspecific
Ultraviolet light Inhibits Langerhans’ cells and the Atopic dermatitis; inflammatory
epidermal immune response dermatosis

Levamisole Alters T cell, monocyte, and neutrophil Limited efficacy in veterinary medicine
function

Acemannan Stimulates macrophages; increases Wound healing; feline

interleukin-1, interleukin-6, tumor necrosis immunodeficiency virus; feline
factor-α, and prostaglandin E2 leukemia virus; select neoplasia;
some tumors

Interferon-α and Stimulates innate immunity; Feline immunodeficiency virus;

interferon-β stimulates immune response nonspecifically feline leukemia virus

als treated with injectable inter-
feron-γ improved substantially
within 14 days and continued to
experience relief from symp-
toms during treatment.21 Inter-
feron-γ is a TH1 cytokine that in-
hibits the exaggerated T H 2
response in allergy. Patients had
minimal side effects during the
6-week course of treatment;
however, most had relapses
when treatment was discontin-
ued.21 Interferon-γ is expensive
and requires frequent injections.
These preliminary results are en-
couraging and suggest that spe-
cific modulation of the immune
system may be used to treat
common diseases.
With chronic infectious dis-
eases involving a TH2 response
that leads to systemic disease
and patient decompensation,
induced T-helper subset switch-
ing can be useful. Cytokines
that are produced by and pro-
mote the TH1 cells inhibit TH2
cells. IL-2 and IL-12 promote
the switch to the protective TH1
subset.6 In mice, chronic leish-
maniasis infection resolved with
IL-12 treatment. 6 The IL-12
may have switched the TH2 re-
sponse associated with chronic
disease to the protective TH1
response, thereby promoting
resolution of the infection. In
diseases in which the TH2 re-
sponse is predominant but inef-
fective (leishmaniasis, AIDS,
candidiasis, and leprosy), IL-12
may be clinically useful.
Staphylococcal vaccines 1
have been used successfully
(50% response) to treat dogs
with recurrent idiopathic bacte-
rial pyoderma and staphylococ-
cal hypersensitivity.23 During
treatment, elevated levels of
TH1 cytokines (IL-1, IL-2, and
interferon-γ) can be identified.24
This apparent stimulation of the
TH1 response is associated with
clinical improvement. As more
clinical trials are performed, ad-
ditional methods that modulate
Small Animal The Compendium January 1997

References
1. Kelso A: TH1 and TH2 subsets:
Paradigms lost? Immunol
Today 16:374–379, 1995.
2. Ramagnani S: Human TH1 and
TH2 subsets: Regulation of dif-
ferentiation and role in protec-
tion and immunopathology. Int
Arch Allergy Immunol 98:279–
285, 1992.
3. Kaye PM: Costimulation and the
regulation of antimicrobial im-
munity. Immunol Today 16:423–
427, 1995.
4. Vries J: Atopic allergy and other
hypersensitivities. Curr Opin
Immunol 6:835–837, 1994.
5. Romagnani S, Maggi E: T H 1
and TH2 responses in AIDS.
Curr Opin Immunol 4:616–622,
1994.
6. Modlin RL: TH1-TH2 paradigm:
Insights from leprosy. J Invest
Dermatol 102:828–831, 1994.
7. Romani L, Mencacci A, Ceni E,
et al: CD4+ subset expression
in murine candidiasis. J Immunol
150:925-931, 1993.
Figure 3—Cutaneous allergy immune response. Langerhans’ cells process and present the antigen to
8. Zhang Y, Cosyns M, Levin MI,
the T-helper 2 (TH2 ) lymphocytes. These lymphocytes produce cytokines (IL-4, IL-5, IL-10, and IL-
et al: Cytokine production in
13), which activate B lymphocytes (B ) and stimulate IgE production. The IgE is bound to the surface varicella zoster virus-stimulated
of the Langerhans’ cells (which enhances antigen recognition) and mast cells (which stimulates aller- limiting dilution lymphocyte
gen-specific degranulation). Mast cells, when stimulated, produce IL-4, which activates more TH2 cultures. Clin Exp Immunol
cells. Keratinocytes injured from the local inflammation and excoriation produce additional inflam- 98:128–133, 1994.
matory mediators. PG = prostaglandin. (From Hnilica KA: The TH2 immune response and the 9. Brett C, Lafferty KJ: The
pathogenesis of allergy. Vet Allergy Clin Immunol 4(4):129, 1996. Modified with permission. ) TH1/TH2 balance in autoimmu-
nity. Curr Opin Immunol 7:793–
798, 1995.
10. Liblau R, Singer S, McDevitt H:
the T-helper cell response may sponse (Table Three). Most of tors is not completely under- TH1 and TH2 CD4+ T cells in
be identified. these compounds cause non- stood; however, T-helper cells the pathogenesis of organ-
Human atopic dermatitis can specific activation of the innate may be involved. specific autoimmune diseases.
Immunol Today 16:34–38,
be treated effectively with cy- immune response. Levamisole is
1995.
closporine, which rapidly allevi- an anthelmintic that activates T Conclusion 11. Klinman DM, Steinberg AD: In-
ates symptoms.20,21 Cyclosporine cells, monocytes, and neu- The identification of T-helper quiry into murine and human
suppresses T-cell function and trophils. It has been used to treat lymphocyte subsets in disease lupus. Immunol Rev 144:157–
downregulates cytokine produc- many diseases but with limited has provided a greater under- 193, 1995.
12. Hafler DA, Weiner HL: Immuno-
tion.20 Unfortunately, however, success.25 A derivative of the aloe standing of the intricate interac-
logic mechanism and therapy in
clinical signs return rapidly when plant, acemannan, seems to pre- tions of the immune system. As multiple sclerosis. Immunol
treatment is discontinued, and dominantly stimulate macro- more diseases are classified on Rev 144:75–107, 1995.
side effects include renal failure phages.25 Results were inconsis- the basis of their lymphocyte re- 13. Mani RN, Elliott MI, Brennan
and hepatic toxicity. Clinical tri- tent when acemannan was used action patterns, novel therapies FM, et al: Monoclonal anti-TNF
alpha antibody as a probe of
als are currently under way to to treat such disorders as de- can be used to alter the funda-
pathogenesis and therapy of
evaluate the effectiveness of a layed wound healing, viral infec- mental immune response asso- rheumatoid disease. Immunol
low dose of cyclosporine used tions (feline leukemia virus and ciated with each disorder. These Rev 144:194–223, 1995.
over a prolonged period to con- feline immunodeficiency virus), new treatments allow practition- 14. Kupiec-Weglinski JW, Wasows-
trol allergic disease.20,21 and tumors (e.g., fibrosarcoma, ers to guide the immune re- ka B, Papp I, et al: CD4 mAB
therapy modulates alloantibody
Immune modulators are used lymphoma, and mast cell tu- sponse toward the optimum re-
production and intracardiac
for various diseases in an at- mors).25 The mechanism of ac- action pattern for any given graft deposition in association
tempt to boost the immune re- tion for most immune modula- disease. with selective inhibition of TH1
The Compendium January 1997
lymphokines. J Immunol
151:5053–5061, 1993.
15. Schlaak IF, Buslau M, Jochum
W, et al: T cells involved in pso-
riasis vulgaris belong to the TH1
subset. J Invest Dermatol
105:145–149, 1994.
16. Niessner M, Volk BA: Altered
TH1/TH2 cytokine profiles in the
intestinal mucosa of patients
with inflammatory bowel dis-
ease as assessed by quantita-
tive reversed transcribed poly-
merase chain reaction (RT-PCR).
Clin Exp Immunol 101:428–
435, 1995.
Small Animal
17. Romagnani S: Regulation of the
diseases. J Allergy Clin sensitivity,” in Antimicrobial
development of type 2 T-helper
Immunol 96:302–318, 1995. Therapy: Applications in Der-
cells in allergy. Curr Opin
21. Rothe MJ, Grant-Kels JM: matology. Trenton, NJ, Veteri-
Immunol 6:838–846, 1994.
Atopic dermatitis: An update. J nary Learning Systems, 1996,
18. Yssel H, Fasler S, Lamb I, et al:
Am Acad Dermatol 35:1–13, pp 21–26.
Induction of non-responsive-
1996. 24. Krishnam G, et al: Cytokines
ness in human allergen-specific
22. Malefyt R, Figdor C, Vries J: Ef- produced by staphage lysate.
type 2 T helper cells. Curr Opin
fects of Interleukin 4 on mono- 12th Europ Immunol Meet
Immunol 6:847–852, 1994.
cyte functions: Comparison to Abstracts:395, 1994.
19. Schall TF, Bacon KS: Chemo-
interleukin 13. The Immunobiol- 25. Kruth SA: Cytokines and biologic
kines, leukocyte trafficking,
ogy of Interleukin 4, 53rd Forum response modifiers in small ani-
and inflammation. Curr Opin
in Immunology, 1993, pp mal practice, in Bonagura JD (ed):
Immunol 6:865–874, 1994.
629–632,. Kirk’s Current Veterinary Therapy.
20. Leung DY: Atopic dermatitis:
23. DeBoer DJ: Understanding and XII. Philadelphia, WB Saunders
The skin as a window into the
treating “staphylococcal hyper- Co, 1995, pp 547–554.
pathogenesis of chronic allergic