Alloreactivity of T Cells

The preceding sections have focused on the role of MHC molecules in the presentation of antigen to T cells and the interactions of TCRs with peptide-MHC complexes. However, as noted in Chapter 7, MHC molecules were first identified because of their role in rejection of foreign tissue. Graft-rejection reactions result from the direct response of T cells to MHC molecules, which function as histocompatibility antigens. Because of the extreme polymorphism of the MHC, most individuals of the same species have unique sets of MHC molecules, or histocompatibility antigens, and are considered to be allogeneic, a term used to describe genetically different individuals of the same species (see Chapter 21). Therefore, T cells respond even to allografts (grafts from members of the same species), and MHC molecules are considered alloantigens. Generally, CD4+ T cells are alloreactive to class II alloantigens, and CD8+ T cells respond to class I alloantigens.

The alloreactivity of T cells is puzzling for two reasons. First, the ability of T cells to respond to allogeneic histocom-patibility antigens alone appears to contradict all the evidence indicating that T cells can respond only to foreign antigen plus sel/-MHC molecules. In responding to allogeneic grafts, however, T cells recognize a /oreign MHC molecule directly. A second problem posed by the T-cell response to allogeneic MHC molecules is that the frequency of allore-active T cells is quite high; it has been estimated that 1%-5% of all T cells are reactive to a given alloantigen, which is higher than the normal frequency of T cells reactive with any particular foreign antigenic peptide plus self-MHC molecule. This high frequency of alloreactive T cells appears to contradict the basic tenet of clonal selection. If 1 T cell in 20 reacts with a given alloantigen and if one assumes there are on the order of 100 distinct H-2 haplotypes in mice, then there are not enough distinct T-cell specificities to cover all the unique H-2 alloantigens, let alone foreign antigens displayed by self-MHC molecules.

One possible and biologically satisfying explanation for the high frequency of alloreactive T cells is that a particular T-cell receptor specific for a foreign antigenic peptide plus a self-MHC molecule can also cross-react with certain allogeneic MHC molecules. In other words, if an allogeneic MHC molecule plus allogeneic peptide structurally resembles a processed foreign peptide plus self-MHC molecule, the same T-cell receptor may recognize both peptide-MHC complexes. Since allogeneic cells express on the order of 105 class I MHC molecules per cell, T cells bearing low-affinity cross-reactive receptors might be able to bind by virtue of the high density of membrane alloantigen. Foreign antigen, on the other hand, would be sparsely displayed on the membrane of an antigen-presenting cell or altered self-cell associated with class I or class II MHC molecules, limiting responsiveness to only those T cells bearing high-affinity receptors.

Information relevant to mechanisms for alloreactivity was gained by Reiser and colleagues, who determined the structure of a mouse TCR complexed with an allogeneic class I molecule containing a bound octapeptide. This analysis revealed a structure similar to those reported for TCR bound to class I self-MHC complexes, leading the authors to conclude that allogeneic recognition is not unlike recognition of self-MHC antigens. The absence of negative selection for the pep-tides contained in the foreign MHC molecules can contribute to the high frequency of alloreactive T cells. This condition, coupled with the differences in the structure of the exposed portions of the allogeneic MHC molecule, may account for the phenomenon of alloreactivity. An explanation for the large number of alloreactive cells can be found in the large number of potential antigens provided by the foreign molecule plus the possible peptide antigens bound by them.

SUMMARY

■ Most T-cell receptors, unlike antibodies, do not react with soluble antigen but rather with processed antigen bound to a self-MHC molecule; certain yS receptors recognize antigens not processed and presented with MHC.

■ T-cell receptors, first isolated by means of clonotypic monoclonal antibodies, are heterodimers consisting of an a and p chain or a y and S chain.

■ The membrane-bound T-cell receptor chains are organized into variable and constant domains. TCR domains are similar to those of immunoglobulins and the V region has hypervariable regions.

■ TCR germ-line DNA is organized into multigene families corresponding to the a, p, y, and S chains. Each family contains multiple gene segments.

■ The mechanisms that generate TCR diversity are generally similar to those that generate antibody diversity, although somatic mutation does not occur in TCR genes, as it does in immunoglobulin genes.

■ The T-cell receptor is closely associated with the CD3, a complex of polypeptide chains involved in signal transduction.

■ T cells express membrane molecules, including CD4, CD8, CD2, LFA-1, CD28, and CD45R, that play accessory roles in T-cell function or signal transduction.

■ Formation of the ternary complex TCR-antigen-MHC requires binding of a peptide to the MHC molecule and binding of the complex by the T-cell receptor.

■ Interactions between TCR and MHC class I/peptide differ from those with MHC class II/peptide in the contact points between the TCR and MHC molecules.

■ The yS T-cell receptor is distinguished by ability to bind native antigens and by differences in the orientation of the variable and constant regions.

■ In addition to reaction with self MHC plus foreign anti-gens,T cells also respond to foreign MHC molecules, a reaction that leads to rejection of allogeneic grafts.

References

Allison, T. J., et al. 2001. Structure of a human 78 T-cell antigen receptor. Nature 411:820.

Gao, G. F., et al. 1997. Crystal structure of the complex between human CD8aa and HLA-A2. Nature 387:630.

Garboczi, D. N., et al. 1996. Structure of the complex between human T-cell receptor, viral peptide, and HLA-A2. Nature 384:134.

Garcia, K. C., et al. 1996. An ap T-cell receptor structure at 2.5 Â and its orientation in the TCR-MHC complex. Science 274:209.

Garcia, K. C., et al. 1998. T-cell receptor-peptide-MHC interactions: biological lessons from structural studies. Curr. Opinions in Biotech. 9:338.

Hayday, A. 2000. 78 Cells: A right time and a right place for a conserved third way of protection. Ann. Rev. Immunol. 18:1975.

Hennecke J., and D. C. Wiley 2001. T-cell receptor-MHC interactions up close. Cell 104:1.

Kabelitz, D., et al. 2000. Antigen recognition by 78 T lymphocytes. Int. Arch. Allergy Immunol. 122:1.

Reinherz, E., et al. 1999. The crystal structure of a T-cell receptor in complex with peptide and MHC class II. Science 286:1913.

Reiser, J-B., et al. 2000. Crystal structure of a T-cell receptor bound to an allogeneic MHC molecule. Nature Immunology 1:291.

Sklar, J., et al. 1988. Applications of antigen-receptor gene rearrangements to the diagnosis and characterization of lym-phoid neoplasms. Ann. Rev. Med. 39:315.

Xiong,Y., et al. 2001. T-cell receptor binding to a pMHCII ligand is kinetically distinct from and independent of CD4. J. Biol. Chem. 276:5659.

Zinkernagel, R. M., and P. C. Doherty. 1974. Immunological surveillance against altered self-components by sensitized T lymphocytes in lymphocytic choriomeningitis. Nature 251:547.

http://imgt.cines.fr

A comprehensive database of genetic information on TCRs, MHC molecules, and immunoglobulins, from the International ImmunoGenetics Database, University of Montpelier, France.

http://www.bioscience.org/knockout/tcrab.htm

This location presents a brief summary of the effects of TCR knockouts.

Study Questions

Clinical Focus Question A patient presents with an enlarged lymph node, and a T-cell lymphoma is suspected. However, DNA

sampled from biopsied tissue shows no evidence of a predominant gene rearrangement when probed with a and p TCR genes.

What should be done next to rule out lymphocyte malignancy?

1. Indicate whether each of the following statements is true or false. If you think a statement is false, explain why.

a. Monoclonal antibody specific for CD4 will coprecipitate the T-cell receptor along with CD4.

b. Subtractive hybridization can be used to enrich for mRNA that is present in one cell type but absent in another cell type within the same species.

c. Clonotypic monoclonal antibody was used to isolate the T-cell receptor.

d. The T cell uses the same set ofV, D, and J gene segments as the B cell but uses different C gene segments.

e. The ap TCR is bivalent and has two antigen-binding sites.

f. Each ap T cell expresses only one p-chain and one a-chain allele.

g. Mechanisms for generation of diversity of T-cell receptors are identical to those used by immunoglobulins.

h. The Ig-a/Ig-p heterodimer and CD3 serve analogous functions in the B-cell receptor and T-cell receptor, respectively.

2. What led Zinkernagel and Doherty to conclude that T-cell receptor recognition requires both antigen and MHC molecules?

3. Draw the basic structure of the ap T-cell receptor and compare it with the basic structure of membrane-bound im-munoglobulin.

4. Several membrane molecules, in addition to the T-cell receptor, are involved in antigen recognition and T-cell activation. Describe the properties and distinct functions of the following T-cell membrane molecules: (a) CD3, (b) CD4 and CD8, and (c) CD2.

5. Indicate whether each of the properties listed below applies to the T-cell receptor (TCR), B-cell immunoglobulin (Ig), or both (TCR/Ig).

a. _Is associated with CD3

b ._Is monovalent c. _Exists in membrane-bound and secreted forms d ._Contains domains with the immunoglobulin-fold structure e. _Is MHC restricted f. _Exhibits diversity generated by imprecise joining of gene segments g. _Exhibits diversity generated by somatic mutation

6. A major obstacle to identifying and cloning TCR genes is the low level of TCR mRNA in T cells.

a. To overcome this obstacle, Hedrick and Davis made three important assumptions that proved to be correct. Describe each assumption and how it facilitated identification of the genes that encode the T-cell receptor.

Go to www.whfreeman.com/immunology I \ Self-Test Review and quiz of key terms b. Suppose, instead, that Hedrick and Davis wanted to identify the genes that encode IL-4. What changes in the three assumptions should they make?

7. Hedrick and Davis used the technique of subtractive hybridization to isolate cDNA clones that encode the T-cell receptor. You wish to use this technique to isolate cDNA clones that encode several gene products and have available clones of various cell types to use as the source of cDNA or mRNA for hybridization. For each gene product listed in the left column of the table below, select the most appropriate.

cDNA and mRNA source clones are from the following cell types: TH1 cell line (A); TH2 cell line (B); TC cell line (C); macrophage (D); IgA-secreting myeloma cell (E); IgG-secret-ing myeloma cell (F); myeloid progenitor cell (G); and B-cell line (H). More than one cell type may be correct in some cases.

8. Mice from different inbred strains listed in the left column of the accompanying table were infected with LCM virus. Spleen cells derived from these LCM-infected mice were then tested for their ability to lyse LCM-infected 51Cr-labeled target cells from the strains listed across the top of the table. Indicate with (+) or ( —) whether you would expect to see 51Cr released from the labeled target cells.

Source of spleen cells from LCM-infected mice

Release of 51Cr from LCM-infected target cells

B10.D2 (H-2d)

B10 (H-2b)

(H-2b/d)

B10.D2 (H-2d)

B10 (H-2b)

BALB/c (H-2d)

BALB/b (H-2b)

9. The 78 T-cell receptor differs from the ap in both structural and functional parameters. Describe how they are similar to one another and different from the B-cell antigen receptors.

Gene product cDNA source mRNA source

IL-2

CDS

J chain

IL-1

CDS

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  • sara weber
    Why is alloreactivity of T cells puzzling for 2 reasons?
    8 years ago

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