Specific Immune Response

Responding to microbial invaders is the responsibility of the immune system . Often, the innate immune
system has the capability to contain the pathogens, but invaders have evolved means to evade innate
immunity. The next line of defense is the adaptive immune system .
 Adaptive immune system Composed of lymphocytes (T helper cells, cytotoxic T cells ) and secreted
proteins ( antibodies produced by B cells )
 Functionality takes days, but once engaged, repeat encounters with the offending agent elicits a faster
response.
 The components, B and T cells , have:
o Diversity: respond to millions of antigens
o Specificity: immune response tailored to the specific antigen
o Memory : can respond many years later
o Recognition: Ability distinguish self and non-self
Adaptive immunity involves the interaction of two major processes in the body, directed by two different
kinds of lymphocytes:
A. Antibody Mediated Immunity (AMI; Humoral Immunity)
B. Cell Mediated Immunity (CMI;)
T CELLS
 T cells represent about 70% of the total lymphocyte population – this varies depending on the
activity of the immune response and can be up to 90%
 all T cells express CD3 on their surfaces, along with T cell receptors (TCRs) which
recognise specific antigens presented in an MHC I or MHC II molecule
 there are numerous different T cell subtypes with different roles, which each have their own
identifiable surface markers:
 helper T cells (CD4) facilitate the activation of the immune response and stimulate division and
differentiation of various effector cells
 cytotoxic T cells (CD8) – also known as killer or effector T cells – provide cell-mediated
immunity by targeting and killing infected cells
 regulatory T cells (CD25 + FOXP3) – also known as suppressor T cells – play a vital role in
limiting the immune response to prevent excessive damage to tissues and organs
 memory T cells (CD62 + CCR7) “remember” what has happened to allow the immune system to
mount a faster, more effective response should the offending organism return

Activation of naive helper T cells

 Following Development in the thymus, these cells (termed recent thymic emigrants (RTE)) progress
from the thymus and home to secondary lymphoid organs (SLO; spleen and lymph nodes).
 Maturation of RTE in SLO results in the generation of mature naive T cells (naïve meaning they have
never been exposed to the antigen that they are programmed to respond to), but naive T cells now lack or
have downregulated (reduced) expression of the RTE-related surface markers, such as CD31, PTK7,
Complement Receptor 1 and 2 (CR1, CR2) and the production of interleukin 8 (IL-8).
 Like all T cells, they express the T cell receptor-CD3 complex. The T cell receptor (TCR) consists of
both constant and variable regions. The variable region determines what antigen the T cell can respond
to.
 CD4+ T cells have TCRs with an affinity for Class II MHC, and CD4 is involved in determining MHC
affinity during maturation in the thymus. Class II MHC proteins are generally only found on the surface
of professional antigen-presenting cells (APCs). MHC class I (in the case of cytotoxic T cells which
express CD8)
 T cells require antigens to be processed into short fragments which form linear epitopes on MHC Class
II (in the case of helper T cells) and MHC Class I (in the case of cytotoxic T cells)
Antigen presentation stimulates naïve CD8+ and CD4+ T cells to become mature "cytotoxic" CD8+ cells
and "helper" CD4+ cells respectively .
 During an immune response, professional antigen-presenting cells (APCs) endocytose antigens
(typically bacteria or viruses), which undergo processing, then travel from the infection site to the lymph
nodes.
 Once at the lymph nodes, the APCs begin to present antigen peptides that are bound to Class II MHC,
allowing CD4+ T cells that express the specific TCRs against the peptide/MHC complex to activate.
Activation signal
 Naïve T cells require at least two signals for activation. Both are provided by an antigen-presenting cell,
which is usually a dendritic cell
 To activate a cytotoxic or helper T cell to proliferate and differentiate into an effector cell, an antigen-
presenting cell provides two kinds of signals.
o Signal 1 is provided by a foreign peptide bound to an MHC protein on the surface of the
presenting cell. This peptide-MHC complex signals through the T cell receptor and its
associated proteins.
o Signal 2 is provided by costimulatory proteins, especially the B7 proteins (CD80 and
CD86), which are recognized by the co-receptor protein CD28 on the surface of the T cell.
 The expression of B7 proteins on an antigen-presenting cell is induced by pathogens during the innate
response to an infection.
 Effector T cells act back to promote the expression of B7 proteins on antigen-presenting cells, creating a
positive feedback loop that amplifies the T cell response.
 Signal 2 is thought to amplify the intracellular signaling process triggered by signal 1.
 If a T cell receives signal 1 without signal 2, it may undergo apoptosis or become altered so that it can no
longer be activated, even if it later receives both signals (Figure below). This is one mechanism by
which a T cell can become tolerant to self antigens.

 Similar mechanisms are involved in activation of cytotoxic T cells.

  Collectively, the T lymphocytes play or facilitate a central role in the orchestration of all functions of
the adaptive immune system and perform four important tasks:
1) promotion of inflammation by cytokine production (Th1 and Th17 cells)
2) helping B lymphocytes (Th2 cells)
3) regulating immunosuppressive responses (T regulatory cells)
4) killing of unwanted target cells (CTL)
5) T cells are dependent on cytokines (soluble proteins released by different cells, which play
overlapping roles in both innate and adaptive immunity).

Humoral adaptive immunity

 Antibody-mediated immunity
 B cells :
o Differentiate into plasma cells, producing antibodies (through the help of T cells )
o Differentiate into memory cells , briskly responding to reinfection
o Act as antigen-presenting cells to T cells (expressing MHC II)
 Antibodies, along with complement, help the cells of the innate system against extracellular,
encapsulated bacteria
 Antibodies can neutralize toxins, such as tetanus toxin , and viruses .
B cell activation

T Cell-Independent Activation of B cells

Activation of B cells without the cooperation of helper T cells is referred to as T cell-independent
activation and occurs when BCRs interact with T-independent antigens. T-independent antigens
(e.g., polysaccharide capsules, lipopolysaccharide) have repetitive epitope units within their
structure, and this repetition allows for the cross-linkageof multiple BCRs, providing the first signal
for activation (Figure ). Because T cells are not involved, the second signal has to come from other
sources, such as interactions of toll-like receptors with PAMPs or interactions with factors from the
complement system.
Once a B cell is activated, it undergoes clonal proliferation and daughter cells differentiate into
plasma cells. Plasma cells are antibody factories that secrete large quantities of antibodies. After
differentiation, the surface BCRs disappear and the plasma cell secretes pentameric IgM molecules
that have the same antigen specificity as the BCRs (Figure ).
The T cell-independent response is short-lived and does not result in the production of memory B
cells. Thus it will not result in a secondary response to subsequent exposures to T-independent
antigens.

 Figure : T-independent antigens have repeating epitopes that can induce B cell recognition and
activation without involvement from T cells. A second signal, such as interaction of TLRs with
PAMPs (not shown), is also required for activation of the B cell. Once activated, the B cell
proliferates and differentiates into antibody-secreting plasma cells.

T Cell-Dependent Activation of B cells

T cell-dependent activation of B cells is more complex than T cell-independent activation, but the
resulting immune response is stronger and develops memory. T cell-dependent activation can occur
either in response to free protein antigens or to protein antigens associated with an intact pathogen.
Interaction between the BCRs on a naïve mature B cell and a free protein antigen stimulate
internalization of the antigen, whereas interaction with antigens associated with an intact pathogen
initiates the extraction of the antigen from the pathogen before internalization. Once internalized
inside the B cell, the protein antigen is processed and
presented with MHC II. The presented antigen is then recognized by helper T cells specific to the
same antigen. The TCR of the helper T cell recognizes the foreign antigen, and the T cell’s CD4
molecule interacts with MHC II on the B cell. The coordination between B cells and helper T cells
that are specific to the same antigen is referred to as linked recognition.
Once activated by linked recognition, T 2 cells produce and secrete cytokines that activate the B cell
and cause proliferation into clonal daughter cells. After several rounds of proliferation, additional
cytokines provided by the T 2 cells stimulate the differentiation of activated B cell clones into
memory B cells, which will quickly respond to subsequent exposures to the same protein epitope,
and plasma cells that lose their membrane BCRs and initially secrete pentameric IgM (Figure ).
After initial secretion of IgM, cytokines secreted by T 2 cells stimulate the plasma cells to switch
from IgM production to production of IgG, IgA, or IgE. This process, called class switching or
isotype switching, allows plasma cellscloned from the same activated B cell to produce a variety of
antibody classes with the same epitope specificity. Class switching is accomplished by genetic
rearrangement of gene segments encoding the constant region, which determines an antibody’s class.
The variable region is not changed, so the new class of antibody retains the original epitope
specificity.
  Figure : In T cell-dependent activation of B cells, the B cell recognizes and internalizes an antigen
and presents it to a helper T cell that is specific to the same antigen. The helper T cell interacts with
the antigen presented by the B cell, which activates the T cell and stimulates the release of cytokines
that then activate the B cell. Activation of the B cell triggers proliferation and differentiation into B
cells and plasma cells.

B cell types
Plasmablast
A short-lived, proliferating antibody-secreting cell arising from B cell differentiation.[1] Plasmablasts
are generated early in an infection and their antibodies tend to have a weaker affinity towards their
target antigen compared to plasma cell.[16] Plasmablasts can result from T cell-independent activation
of B cells or the extrafollicular response from T cell-dependent activation of B cells.
Plasma cell
A long-lived, non-proliferating antibody-secreting cell arising from B cell differentiation.[1] There is
evidence that B cells first differentiate into a plasmablast-like cell, then differentiate into a plasma
cell.[16] Plasma cells are generated later in an infection and, compared to plasmablasts, have
antibodies with a higher affinity towards their target antigen due to affinity maturation in the
germinal center (GC) and produce more antibodies.[16] Plasma cells typically result from the
germinal center reaction from T cell-dependent activation of B cells, though they can also result from
T cell-independent activation of B cells.[23]
Lymphoplasmacytoid cell
A cell with a mixture of B lymphocyte and plasma cell morphological features that is thought to be
closely related to or a subtype of plasma cells. This cell type is found in pre-malignant and malignant
 plasma cell dyscrasias that are associated with the secretion of IgM monoclonal proteins; these
dyscrasias include IgM monoclonal gammopathy of undetermined significance and Waldenström's
macroglobulinemia.[27]
Memory B cell
Dormant B cell arising from B cell differentiation.[1] Their function is to circulate through the body
and initiate a stronger, more rapid antibody response (known as the anamnestic secondary antibody
response) if they detect the antigen that had activated their parent B cell (memory B cells and their
parent B cells share the same BCR, thus they detect the same antigen). Memory B cells can be
generated from T cell-dependent activation through both the extrafollicular response and the
germinal center reaction as well as from T cell-independent activation of B1 cells.
B-2 cell
FO B cells and MZ B cells.
Follicular (FO) B cell (also known as a B-2 cell)
Most common type of B cell and, when not circulating through the blood, is found mainly in the
lymphoid follicles of secondary lymphoid organs (SLOs).[16] They are responsible for generating the
majority of high-affinity antibodies during an infection.
Marginal-zone (MZ) B cell
Found mainly in the marginal zone of the spleen and serves as a first line of defense against blood-
borne pathogens, as the marginal zone receives large amounts of blood from the general
circulation.[29] They can undergo both T cell-independent and T cell-dependent activation, but
preferentially undergo T cell-independent activation.[16]
B-1 cell
Arises from a developmental pathway different from FO B cells and MZ B cells.[28] In mice, they
predominantly populate the peritoneal cavity and pleural cavity, generate natural antibodies
(antibodies produced without infection), defend against mucosal pathogens, and primarily exhibit T
cell-independent activation.[28] A true homologue of mouse B-1 cells has not been discovered in
humans, though various cell populations similar to B-1 cells have been described.[28]
Regulatory B (Breg) cell
An immunosuppressive B cell type that stops the expansion of pathogenic, pro-inflammatory
lymphocytes through the secretion of IL-10, IL-35, and TGF-β. Also, it promotes the generation of
regulatory T (Treg) cells by directly interacting with T cells to skew their differentiation towards
Tregs. No common Breg cell identity has been described and many Breg cell subsets sharing
regulatory functions have been found in both mice and humans. It is currently unknown if Breg cell
subsets are developmentally linked and how exactly differentiation into a Breg cell occurs. There is
evidence showing that nearly all B cell types can differentiate into a Breg cell through mechanisms
involving inflammatory signals and BCR recognition.
There are two types of the immune response:
 Primary Immune Response
 Secondary Immune Response