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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 lesions (Wucherpfennig, K. W., et. al. PNAS 89:4588).

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t cells in autoimmune and infectious disease
 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 89:4588).
  •  T cells expand from 5 to 17% of PBMCs in patients during acute stages of P. Falciparum (Ho, M. et. al. Infect Immun. 62: 855–862).
  • Similar  T cell expansion has been observed in M. Tuberculosis infection and Chron’s disease.
gram positive nocardia asteroides causes lethal infection in t cell ko mice
Gram-positive Nocardia asteroides Causes Lethal Infection in  T Cell KO Mice

Tam et. al., Infection & Immunity, 2001 69:6165.

lung sections of mice infected with aerosolized gram positive n asteroides
Lung Sections of Mice Infected with Aerosolized Gram-positive N. asteroides

B6

-/- KO

 Neutrophils in -/- mice

N. asteroides (dark blue stain)

Tam et. al., Infection & Immunity, 2001 69:6165.

ko mice reveal a unique role for gamma delta t cells6
 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 mice—which usually die upon infectious challenge.
  • Skin wound healing is impaired.
t cells distribute differently then t cells

Skin (V5 V1)

Reproductive Tract

Respiratory Tract

Small Intestine (IELs)

 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
slide9

Ag

Ag

CDR3 Length Distribution of Immune Receptor Chains

B cell receptor

 T cell receptor

MHC

 T cell receptor

?

Ed Rock, et. al.

slide11

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.

significance of ie k recognition
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.
what do gamma delta tcrs recognize13
What do Gamma Delta TCRs Recognize?
  • MHC class II, IEk
  • HSV-gI envelope protein
slide14

HSV-1

gI envelope protein is left on the cell surface

Viral DNA

tgi4 t cell clone is stimulated by plate bound hsv gi protein
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 185:1969

significance of hsv gi interaction
Significance of HSV-gI Interaction?
  • Like B cell Ig receptors,  TCRs can recognize protein directly without need for processing and presentation upon MHC molecules.
slide17

TgI4

Cytolitic activity

 T Cell

TCR

V

V

C

C

HSV-1

gI envelope protein is left on the cell surface

Viral cDNA

what do gamma delta tcrs recognize18
What do Gamma Delta TCRs Recognize?
  • MHC class II, IEk
  • gI HSV envelope protein
  • Non-classical MHC T22/T10
t22 tetramer binds high frequencies of t cells
T22 Tetramer Binds High Frequencies of  T Cells

Non-immunized mice

T22 tetramer

  • T22 can’t 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, 287:314

significance of t22 recognition
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.
slide21

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

what do gamma delta tcrs recognize22
What do Gamma Delta TCRs recognize?
  • MHC class II, IEk
  • gI HSV envelope protein
  • Non-classical MHC T22/T10
  • Small phosphate antigens
small alkyl phosphate antigens are secreted by bacteria and also expressed in mammalian tissues
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, 295:2255-8).
  • 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. 161:286)
  • Cell contact is required (Morita, Immunity 3:495).
  • No processing is required (fixed cells + small phosphate antigen = stimulation) (Morita, Immunity 3:495).
significance of small phosphate tcr recognition
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 264:267).
  • Suggesting that  T cells monitor cellular stress.
other reports of tcr ligands
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. 169:1236).
  • 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.
t cell summary
 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.
slide27

 T Cell

T22

Small phosphate antigens

‘Non-homeostatic’ Cell

V

V

C

C

Viral derived surface Antigens

LPS

Cell

ii invariant tcr t cells
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.
invariant nk t cells ink t cells
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.
v tcr sequences of cd1d restricted ink t cells
V TCR sequences of CD1d restricted iNK T cells

Lantz, O. and Bendelac, A., J. Exp. Med. 180:1097, 1994.

what do the ink t cells recognize
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. 2:971).
galactosylceramide and ink t cells

-carbon linkage

-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.

ink t cells are specific for cd1d1 galcer
iNK T cells are specific for CD1d1 -Galcer

Loaded with a-Galcer

Not preloaded

CD1d tetramer

TCR 

ink t cell function
iNK T cell function
  • Rapidly (within 1-2 hours) secrete IFN- and/or IL-4 upon stimulation in vivo (Yoshimoto T J. Exp. Med. 179:1285).
  • J281-/- mice lack iNK T cells and have delayed immune responses to a variety of infectious agents.
dendritic epidermal t cells detcs promote wound healing
Dendritic Epidermal  T cells (DETCs) promote wound healing

-/-

B6

Jameson et. al. Science 296:747

what is the detc tcr ligand
What is the DETC TCR ligand?
  • We don’t know….
  • Heat shocked keratinocytes stimulate DETC cells in a TCR dependent fashion (Haravan, W. Science 252:1430).
  • This ligand is not sensitive to trypsin treatment (unpublished results), therefore is most likely not a protein.
first line of defense
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?