Protective immunity and model antigensPROTECTIVE
IMMUNITY AND MODEL ANTIGENS
In immunology the most meaningful readout for immunity are :
protection against infection
protection against established tumors
Nevertheless, in vitro measurements all provide relatively reliable
surrogates for measuring immunity, providing we keep in mind that
each measures distinct parameters and each has a different threshold of
detection.
cellular proliferation
cytokine production
cytotoxic activity
tetramer or antigen binding
Causes of discrepant experimental results in measuring immune responses
:
often neither the number of antigenic determinants measured and recognized
by B or T cells nor the involved receptor specifities are well defined.
although infectious agents express hundreds to thousands of determinants
...
they expose on the surface of infected cells only one or a few antigenic
sites that are relevant for recognition by the host's T cell pool.
on the intact infectious agents, only one or few antigenic determinants
are exposed that are both important for virus infection and are accessible
to B cell receptors and protective antibodies. Eg in VSV
the only determinant exposed on the surface is the tip of the glycoprotein
to which the neutralizing antibody binds and because of size restrictions,
only one antibody can bind at a time. Other antibodies cannot bind determinants
that lie between the glycoproteins or inside the virus particle. Isolated
purified glycoprotein of VSV has several antigenic sites, including the
tp exposed on the intact virus particle. The other determinants can bind
antibodies that have been generated during a VSV infection against fragments
of the envelope and against released glucoprotein. These additional antibody
specificities can be measured experimentally in a binding assay. However,
only antibodies specific for the tip are protective. Thus, antibody responses
measured to isolated proteins measure polyspecific and polyclonal antibody
responses. In contrast, virus-neutralizing antibody responses are mono-
or oligo-specific and often oligoclonal.
For example, immunity against a given strain of poliovirus
or dengue virus
cannot protect against other strains. Therefore, although most specificities
of B and T cells induced are the same for all strains, only the neutralizing
(protective) antibodies define specificity of immunity. In contrast to
protective determinants on infectious agents or toxins, model antigens
often used in immunological research expose multiple (between 10 and 1000)
antigenic sites on particular proteins, or in mixed antigen preparations.
Similarly,
similarly, although only one or few specific T cell epitopes are expressed
by infectious agents in the context of one individual's MHC haplotype,
basic immunological studies often examine T cell responses against multiple
minor or major histocompatibility differences that represent hundreds to
thousands of different T cell epitopes. Thus, polyspecificity and polyclonality
of T or B cell responses may suggest specific responses that in fact reflect
cross-reactivity.
available TcR and BcR repertoire and respective receptor frequencies.
The immune repertoire can probably offer efficient protection against about
103 to 104 distinct infections relevant for the survival
of a given species. Thus in mice about 1 to 5 x 107 each of
mature CD8+ T, CD4+ T, or B cells exists and immunity
is generated from a starting number of about 100 to 1000 antigen-specific
precursor T and B cells. If the frequency of the specific lymphocytes were
much lower, induction of an immune response would be too slow to be protective.
On the other hand, if it increases above 10-3 to 10-2,
then activation becomes less controllable because of nonspecific bystander
effects, which can influence the immune response. This potential problem
is borne out by studies using experimental mice that express very high
precursor frequencies of specific transgenic T cells to study crosspriming,
tolerance, or memory. For example, bacterial infection of TcR transgenic
mice bearing an unrelated receptor specificity can result in T cell activation
via nonspecific bystander effectsRef1,
Ref2,
and Ref3.
last but not least, tendency to use specific
pathogen-free (SPF)
experimental animals raised under nonphysiologically clean conditions may
skew the specificity of reactivity due to reduced nonspecific, concomitant
immunity and unwanted bystander effects.
Discrepancies between the immunology of model antigens and immunity against
infections may eventually be resolved by more stringent definition of relevant
characteristics of the chosen experimental system.
the only determinant exposed on the surface is the tip of the glycoprotein
to which the neutralizing antibody binds and because of size restrictions,
only one antibody can bind at a time. Other antibodies cannot bind determinants
that lie between the glycoproteins or inside the virus particle. Isolated
purified glycoprotein of VSV has several antigenic sites, including the
tp exposed on the intact virus particle. The other determinants can bind
antibodies that have been generated during a VSV infection against fragments
of the envelope and against released glucoprotein. These additional antibody
specificities can be measured experimentally in a binding assay. However,
only antibodies specific for the tip are protective. Thus, antibody responses
measured to isolated proteins measure polyspecific and polyclonal antibody
responses. In contrast, virus-neutralizing antibody responses are mono-
or oligo-specific and often oligoclonal.
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