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I.  T Cells II. Invariant TCR T Cells

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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I.  T Cells II. Invariant TCR T Cells

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  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 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.

  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 69:6165.

  5. 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.

  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 mice—which usually die upon infectious challenge. • Skin wound healing is impaired.

  7. 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

  8. What do Gamma Delta TCRs recognize?

  9. Ag Ag 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 185:1969

  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. TgI4 Cytolitic activity  T Cell TCR V V C C 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 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

  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, 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).

  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 264:267). • 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. 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.

  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.  T Cell T22 Small phosphate antigens ‘Non-homeostatic’ Cell V V C C Viral derived surface Antigens 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. 180:1097, 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. 2:971).

  32. -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.

  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. 179:1285). • 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 296:747

  36. 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.

  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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