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I. ?? T Cells II. Invariant TCR T Cells

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I. T Cells II. Invariant TCR T Cells T Cells in Autoimmune and Infectious Disease T cells can account for 30% of the T cell infiltrate in MS ... – PowerPoint PPT presentation

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Title: I. ?? T Cells II. Invariant TCR T Cells


1
I. ?? T Cells II. Invariant TCR T Cells
2
?? T Cells in Autoimmune and Infectious Disease
  • ?? T cells can account for 30 of the T cell
    infiltrate in MS lesions (Wucherpfennig, K. W.,
    et. al. PNAS 894588).
  • ?? T cells expand from 5 to 17 of PBMCs in
    patients during acute stages of P. Falciparum
    (Ho, M. et. al. Infect Immun. 62 855862).
  • Similar ?? T cell expansion has been observed in
    M. Tuberculosis infection and Chrons disease.

3
?? KO Mice Reveal a Unique role for Gamma Delta T
Cells
  • Infections agents can be lethal

4
Gram-positive Nocardia asteroides Causes Lethal
Infection in ?? T Cell KO Mice

Tam et. al., Infection Immunity, 2001 696165.
5
Lung Sections of Mice Infected with Aerosolized
Gram-positive N. asteroides
?-/- KO
B6
? Neutrophils in ?-/- mice
N. asteroides (dark blue stain)
Tam et. al., Infection Immunity, 2001 696165.
6
?? KO mice reveal a unique role for Gamma Delta T
cells
  • Certain infections can be lethal.
  • Most infections reveal inflammatory defects in ??
    KO mice.
  • Pathological outcome is different than that of ??
    KO micewhich usually die upon infectious
    challenge.
  • Skin wound healing is impaired.

7
?? T Cells Distribute Differently Then ?? T Cells
  • Anatomically located lining the epithelial
    tissues
  • Small numbers (1-2 of cells) found in the
    lymphoid tissues, spleen and lymph nodes
  • ?? might play a role early in the immune response

8
What do Gamma Delta TCRs recognize?
9
CDR3 Length Distribution of Immune Receptor Chains
B cell receptor
?? T cell receptor
MHC
?? T cell receptor
?
Ed Rock, et. al.
10
What do Gamma Delta TCRs recognize?
  • MHC class II, IEk.

11
LBK5 ?? T cell clone recognizes backbone
residues of class II IEk and recognition is
independent of the presented peptide.
Important residues for LBK5 stimulation
LBK5 was generated from immunization with
non-MHC matched splenocytes.
12
Significance of IEk Recognition?
  • Unlike MHC restricted ?? T cell clones, peptide
    does not confer reactivity of LBK5 to IEk.
  • Gamma delta T cells recognize antigens in a
    fundamentally different way than ?? T cells.
  • Gamma delta development seems to be normal in
    b2m-/- and MHC II negative mice, which suggest
    that the many of the ?? TCR ligands are not
    conventional MHC molecules.

13
What do Gamma Delta TCRs Recognize?
  • MHC class II, IEk
  • HSV-gI envelope protein

14
HSV-1
gI envelope protein is left on the cell surface
Viral DNA
15
TgI4 ?? T Cell Clone is Stimulated by Plate
Bound HSV-gI Protein
Cell lysis blocked by ?-TCR and ?-gI mAbs.
TgI4 was recovered from mice inoculated (I.V.)
with HSV-1.
Sciammas, R. et. al. J. Exp. Med 1851969
16
Significance of HSV-gI Interaction?
  • Like B cell Ig receptors, ?? TCRs can recognize
    protein directly without need for processing and
    presentation upon MHC molecules.

17
HSV-1
gI envelope protein is left on the cell surface
Viral cDNA
18
What do Gamma Delta TCRs Recognize?
  • MHC class II, IEk
  • gI HSV envelope protein
  • Non-classical MHC T22/T10

19
T22 Tetramer Binds High Frequencies of ?? T Cells
Non-immunized mice
T22 tetramer
  • T22 cant present antigens because of its
    truncated MHC ? barrel.
  • T22 is upregulated on APCs upon CFA immunization
    or LPS stimulation.
  • Affinity measurements can be made between G8 ??
    TCR and T22.

?? TCR
Crowley, M. et. al. Science 2000, 287314
20
Significance of T22 Recognition?
  • Self or natural ligand
  • This ligand is not recognized by ?? TCRs,
    suggesting that the ?? TCR recognize
    non-overlapping cues through the ?? TCR.

21
Significance of T22 Recognition?
T cell Status of immune system Frequency1 T10/T22
- specific gd T cells 1/250 MHC/peptide
specific ab T cells (not primed)
1/1,000,000 MHC/peptide specific ab T
cells (Immunized effector phase) 1/2-1/100

High frequencies fast immune responses to
ligand
22
What do Gamma Delta TCRs recognize?
  • MHC class II, IEk
  • gI HSV envelope protein
  • Non-classical MHC T22/T10
  • Small phosphate antigens

23
Small Alkyl-Phosphate Antigens are Secreted by
Bacteria and Also Expressed in Mammalian Tissues.
  • Small phosphate antigens stimulate human and
    monkey V?2 V?2 T cells (Shen, Science,
    2952255-8).
  • V?2 V?2 T cells expand (15-60) in response to a
    variety of infectious agents.
  • Reactivity is mediated through the ?? TCR and the
    CDR3 is important for reactivity (Bukowski, J. I.
    161286)
  • Cell contact is required (Morita, Immunity
    3495).
  • No processing is required (fixed cells small
    phosphate antigen stimulation) (Morita,
    Immunity 3495).

24
Significance of Small Phosphate ?? TCR
Recognition?
  • Ligands can either be self or foreign.
  • Small phosphates are produced by the nucleotide
    salvage pathway, during cellular stress (i.e.
    heat shock, starvation, etc.) (Constant, P.
    Science 264267).
  • Suggesting that ?? T cells monitor cellular
    stress.

25
Other Reports of ?? TCR Ligands
  • MICA a non classical MHC that is upregulated on
    tumor cells and upon heat shock (Wu, J. et. al.
    J. I. 1691236).
  • CD1c- No addition of antigen is required (Spada F
    et. al. JEM March 2000).
  • Hsp60 has been reported to be stimulatory.
  • Qa-1b can stimulate ?? T cells.

26
?? T Cell Summary
  • ?? T cells can recognize self (MHC and MHC-like)
    and foreign ligands (HSV-gI, small phosphate
    antigens).
  • Many of the ligands are up regulated on the
    surface of cells upon infection or stress.
  • Taken together ?? T cells might see cell
    surface perturbations in homeostasis through
    their TCR and regulate the immune response.

27
LPS
Cell
28
II. Invariant TCR T cells.
  • Invariant TCR T cells clonally/oligoclonally
    express TCRs with a limited P/N/Junctional CDR3
    diversity.
  • High frequencies are found in specific tissues.
  • NK T cells, DETC ?? T cells, MAIT cells.

29
Invariant NK T cells (iNK T cells)
  • Defined as being reactive to CD1d.
  • Express the invariant V? and limited V? TCRs.
  • iNK T cells represent the majority of T cells
    found in the liver.
  • 1-3 found in the spleen.
  • Express markers found on NK cells.

30
V? TCR sequences of CD1d restricted iNK T cells
Lantz, O. and Bendelac, A., J. Exp. Med.
1801097, 1994.
31
What do the iNK T cells recognize?
  • CD1d plus.
  • An unidentified endogenous self-glycolipid
    antigen.
  • ?-GlcCer synthase KO APCs fail to stimulate
    galcer/CD1d1 restricted NK T cells (Stanic et al.
    PNAS, 2003).
  • Selected by CD1, CD8, CD4, positive cells in the
    thymus (Nat Immunol. 2971).

32
?-Galactosylceramide and iNK T cells
  • CD1 family of B2m dependent class Ib proteins
    that can present a variety of lipid antigens to
    CD1 restricted T cells.
  • 80 of NK T cells (NK1.1) in both mouse and
    human express an invariant TCR (mV?14-J?281,
    hV?24-J?Q) that recognize CD1d loaded with
    ?-GalCer.
  • Mammalians do not synthesize ?-GalCer which is
    derived from sea sponges.

?-Galcer is likely a structural mimic of a self
or natural ligand.
33
iNK T cells are specific for CD1d1 ?-Galcer
Loaded with a-Galcer
Not preloaded
CD1d tetramer
TCR ?
34
iNK T cell function
  • Rapidly (within 1-2 hours) secrete IFN-? and/or
    IL-4 upon stimulation in vivo (Yoshimoto T J.
    Exp. Med. 1791285).
  • J?281-/- mice lack iNK T cells and have delayed
    immune responses to a variety of infectious
    agents.

35
Dendritic Epidermal ?? T cells (DETCs) promote
wound healing
?-/-
B6
Jameson et. al. Science 296747
36
What is the DETC TCR ligand?
  • We dont know.
  • Heat shocked keratinocytes stimulate DETC cells
    in a TCR dependent fashion (Haravan, W. Science
    2521430).
  • This ligand is not sensitive to trypsin treatment
    (unpublished results), therefore is most likely
    not a protein.

37
Table summarizing invariant T cell phenotypes
38
First line of Defense
  • Invariant and gamma delta T cells respond quickly
    to antigenic stimulus.
  • Should these T cells be classified as being apart
    of the innate immune system or not?
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