7 - Cell-Mediated Immunity Flashcards
Cell mediated immunity protects against what type of pathogens? What mediates it? What other cells are required?
Intracellular.
Mediated by T lymphocytes.
Requires phagocytes, infected host cells, B lymphocytes to interact with T cell.
How does the immune system recognize and discriminate self from non-self?
The T cell receptors (TCR)
What is an epitope?
The part of a peptide antigen that’s recognized by the TCR (T cell receptor)
Theses are the peptides displayed by MHC molecules.
What are the key concepts regarding TCRs?
Variable region
Constant region: genetically fixed
Affinity: fixed
What are the two types of TCRs?
alphabeta T cells: most abundant and MHC restricted
gammadelta T cells: common in gut mucosa and skin epidermis, not MHC restricted
How can T cells of the adaptive immune system change or adapt to differences in self or non-self antigens?
They modify the TCR through somatic recombination.
What is the organization of TCR beta chains?
Has diversity region (D), joining region (J), and variable region (V).
What is the organization of TCR alpha chains?
Has variable region (V) and joining region (J).
What is the important protein involved in somatic recombination in the germline DNA of the TCR beta chain? What happens if theres a mutation in this protein?
RAG 1/2 which recombines and splices exons.
Mutation results in the inability to to recombine C, D, and J regions and you don’t get T cells (ie no response to bacteria or viruses).
What is TCR allelic exclusion? What else must occur for a TCR chain to be expressed?
Expression of TCRbeta chain gene of EITHER the maternal or paternal chromosome NOT both.
All recombination events must be in the proper reading frame. Whatever isn’t in the frame will not rearrange and won’t be in the gene product.
What is TCR hypervariability? What does this region encode? Why is it important?
Regions of genetic variability within the TCR.
Complimentary-determining region (CDR) encodes variable regions of the TCR B and a chain.
Why are the hypervariable regions of the TCR important? Why is it good that they are highly variable?
Because they encode the amino acids that come into contact with the linear peptide in the MHC molecule (they do the recognition and binding to the peptide fragment.)
You want them to be very different so they can recognize lots of different peptides presented to them .
What two factors contribute to antigenic variability?
Combinatorial: variation amongst possible exon combinations
Junctional: removal of nucleotides and addition of nucleotides by Tdt enzyme as it recombines exons together; and during strand repair.
Where do T lymphocytes start their development?
In the bone marrow as common lymphoid progenitors.
IL7 helps them divide and become Pro-T cells.
What is the first checkpoint in T lymphocyte development?
Going from a Pro-T cell to a Pre-T cell.
To do this it must express at least one chain of the antigen receptor (beta or alpha) and if not it will undergo cell death.
What is the second checkpoint in T lymphocyte development?
Going from a Pre T cell to a Immature T cell.
To do this it must express a complete antigen receptor (both alpha and beta chain combined into an intact TCR).
Failure to do so results in cell death.
What is the third checkpoint in T lymphocyte development?
Screening the TCRs based on how they react to self/non-self:
Weak recognition of class I or II +peptide = positive selection
No recognition of MHC + peptide: death by neglect
Strong recognition of class I or II + peptide: negative selection
What is central tolerance? What happens without this?
Specific unresponsiveness against SELF antigens.
Without central tolerance you get autoimmunity.
What is AIRE and what is its function? What happens when T cells come into contact with MHC loaded with the products of AIRE?
A TF that drives the expression of SELF proteins and is an autoimmune regulator in medullary epithelial cells.
MHC loaded with self peptides undergo negative selection and be killed. This makes sense because you don’t want T cells to react with MHC complexed with self (causes autoimmunity if these cells aren’t killed).
Mutations in RAG 1 and 2 causes what?
What does a lack of a thymus cause?
SCID: severe combined immunodeficiency
DiGeorge Syndrome: no T cells.
What can result from mutations in AIRE?
APECED: autoimmun polyendocrinopathy with candidiasis and ectodermal dysplasia.
Result is lack of T cell negative selection which causes auto-selective T cells in your organs (autoimmune disease).
Your pt is a 3 yo F presenting with recurrent bacterial infections. A CBC shows a significant decrease in effector T cells in the pts peripheral blood. A loss of function mutation in which gene would most likely account for the pts lymphopenia?
IL-7 because it’s involved in T cell development and proliferation.
What are the two phases of cell-mediated immunity?
Induction phase in the lymphatic tissues.
Effector phase in the peripheral tissues.
How do T cells protect the body from pathogens or non-self antigens?
Signaling through TCR and immune synapse.
What are the four steps of T cell activation?
- Antigen recognition
- Activation and clonal expansion
- Differentiation
- Effector functions
What is the first signal required for the antigen recognition stage of T cell activation (step 1 of the induction phase)?
Signal 1: TCR-MHC peptide, CD4 or CD8 co-receptor on T cell, CD3, Zeta chains (CD3 and Zeta chain have ITAM motif for activation )
CD28
