T cells and Cell-mediated Immunity
Recall:
 two major components of the immune system:
o innate immunity – non-specific phagocytosis and inflammation
o acquired immunity – antigen-specific B and T lymphocyte responses
 two major types of immune responses
o humoral immunity – proteins dissolved in blood and lymph (eg. antibodies,
complement) bind to extracellular pathogens and toxins
o cell-mediated immunity – immune cells (eg. cytotoxic T lymphocytes, natural
killer cells) attack and destroy extracellular pathogens, and cells infected with
intracellular pathogens
 T lymphocytes are important in all parts of the immune response because they
o can recognize and respond to specific antigens, either by attacking infected cells
directly or by activating other immune cells via cytokines & cell-cell interactions
The life story of a T-lymphocyte:
Childhood – growing up in the bone marrow
 hematopoietic stem cell  common lymphoid progenitor  Tcell precursor (thymocyte)
Adolescence – moving to the thymus for maturation and ‘training’
 thymocyte arrives in the thymic cortex (TCR- CD4- CD8-, “double negative”)
 undergoes genomic rearrangement in order to form a unique and functional T-cell
receptor gene (TCR+)
 learns to express both co-receptors (CD4+ CD8+ , “double positive”)
 positive selection – only cells whose TCR recognizes self MHC survive
 chooses one co-receptor (CD4+ or CD8+ , “single positive”)
 negative selection – cells who are too self-reactive are killed
 the 2% who survive the whole process continue on into the thymic medulla
 from here, the mature T cells can enter the bloodstream
Early Adulthood – traveling throughout the blood, lymph and tissues
 naïve T cells circulate back and forth between blood and peripheral lymphoid tissue until
they encounter an MHC-peptide complex on an antigen-presenting cell (APC) that they
can bind particularly well
 when this binding happens, they are activated and transformed into effector T cells
(‘priming’)
Late Adulthood – proliferating and working
 activated T cells proliferate rapidly, forming a population of cells specific to the antigen
in question
 these cells play an important role in the immune response, which varies based on the type
of effector cell they become
o CD8+  cytotoxic T cells (kill infected cells)
o CD4+  TH1 cells (activate infected macrophages) or TH2 cells (activate antigenspecific B cells to make antibodies)
Old Age – cell death and immunological memory
 once the infection has passed, most of the effector cells undergo apoptosis
 some, however, become long-lived memory cells, which can be re-activated in case of
subsequent infection
The Major Histocompatibility Complex (MHC)
 the MHC is a cluster of genes on chromosome 6 (or chromosome 17, if you’re a mouse)
that encode important immune proteins
 the genes in the cluster are divided into 3 classes
o Class I MHC proteins present cytosolic peptides to T cells
o Class II MHC proteins present exogenous (endocytic) peptides to T cells
o Class III includes a variety of other molecules (TNFα and β, complement
components, heat shock proteins, steroid 21-hydroxylases)
 MHC Class I and II proteins are polygenic
o in humans, the 3 class I genes are called HLA A, B and C
o and the 3 class II genes are called HLA DP, DQ and DR
 MHC Class I and II proteins are polymorphic
o within the population, there are many possible alleles for each of the HLA genes
 the particular arrangement of MHC alleles found on a given chromosome is called a
haplotype
o the MHC genes are very closely linked on the chromosome, and tend to be
inherited as a unit – so you get a haplotype from each parent
o these genes are co-dominantly expressed, so you’ll express the alleles from both
parents at once
 the two MHC classes have different structures and functions:
MHC Class I
heavy chain + β2-microglobulin
found on most nucleated cells
binds peptides from the cytoplasm
binding at the ends of the groove
binds peptides 8-10 amino acids long
displays to CD8+ T cells
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MHC Class II
α-chain + β-chain
found only on antigen-presenting cells
binds peptides from endosomes
binding along the sides of the groove
binds peptides 10-25 amino acids long
displays to CD4+ T cells
in both MHC classes, two of the protein domains form a peptide-binding groove
this groove is able to bind a wide variety of peptides, because it forms hydrogen-bonds
with the peptide bonds connecting the amino acids, rather than with the individual amino
acids themselves
at the same time, each kind of MHC molecule has a preference for a particular group of
peptides, based on the presence of certain amino acid side chains (‘anchor residues’)
which fit into the ‘specificity pockets’ in the groove of that molecule
Class I MHC molecules bind cytosolic peptides and present them to CD8+ T cells
o healthy cells present normal self peptides (eg. from ribosomes, histones,
cytochromes, etc.), which the T cells know to ignore
o infected cells present foreign viral proteins, which elict a cytotoxic T cell
response to kill the infected cell
Class II MHC molecules bind endosome peptides and present them to CD4+ T cells
o the APC internalizes the pathogen via phagocytosis or endocytosis
o in the endosome, the pathogen is killed and broken down into peptides
o the peptides bind to Class II MHC molecules, and are presented on the cell
surface where they can elicit a helper T cell response (resulting in macrophage
activation and/or cytokine production)
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T cells that make it out of your thymus are ‘MHC restricted’ – that is, they only respond
to antigenic peptides if they’re displayed on your particular kinds of MHC molecules
so your haplotype determines what kinds of peptides your cells can display to passing T
cells, and thus it helps determine the kind of immune response you’ll have to a given
pathogen
this can be clinically relevant, since things like ragweed allergy and autoimmune diseases
(eg. Grave’s disease, Type I diabetes, rheumatoid arthritis, etc.) can be linked to
particular MHC alleles
T Cell Receptor (TCR)
 recall: each B cell expresses a unique immunoglobulin molecule, with a particular antigenic
specificity – this is accomplished by randomly recombining heavy and light chain genes at
the genomic (DNA) level
 a similar process occurs in T cells, where each cell randomly recombines its TCR α and β
genes to produce a unique TCR molecule with a particular MHC+peptide specificity
 first the β chain undergoes VDJ recombination
 if that’s successful, the α chain undergoes VJ recombination
 if that’s successful, the cell expresses a mature α β TCR and can undergo positive and
negative selection
 positive selection results in MHC restriction
 negative selection results in self-tolerance
 note:  T cells also exist, but they only constitute 1% of blood lymphocytes and have limited
diversity so we don’t pay much attention to them
T cell self-tolerance
 in the thymus, dendritic cells display normal MHC+peptide combinations to the developing
T cells
 any T cells which are activated by these self-antigens are made to undergo apoptosis
 however, there must be some MHC+peptide combinations that are normal in some parts of
the body but aren’t found in the thymus – why don’t we react to those?
 answer: naïve T cells require more than just binding to MHC+peptide in order to become
activated and stimulate an immune response
 they need a co-stimulatory signal, which occurs when a B7 molecule on the APC binds to a
CD28 molecule on the T cell
 once they have become properly activated by the co-stimulatory signal, future interactions
only require the TCR to MHC+peptide binding in order to provoke a response
 the co-stimulatory signal is typically provided by dendritic cells, which only express lots of
the B7 molecule and MHC in response to an inflammatory stimulus (eg. bacterial LPS)
 so, T cells only get activated when there is already an inflammatory reaction in progress
 eg. the need for adjuvents in vaccines in order to get a decent immune response
 also, naïve T cells may be ‘ignorant’ of self-antigens, but if something stimulates them to
become effector T cells, they will have lower thresholds and may respond
 eg. viral infection that triggers an auto-immune reaction