SelfMHC Restriction of T Cells

Both CD4+ and CD8 + T cells can recognize antigen only when it is presented by a self-MHC molecule, an attribute called self-MHC restriction. Beginning in the mid-1970s, experiments conducted by a number of researchers demonstrated self-MHC restriction in T-cell recognition. A. Rosenthal and E. Shevach, for example, showed that antigen-specific proliferation of Th cells occurred only in response to antigen presented by macrophages of the same MHC haplotype as the T cells. In their experimental system, guinea pig macrophages from strain 2 were initially incubated with an antigen. After the "antigen-pulsed" macrophages had processed the antigen and presented it on their surface, they were mixed with T cells from the same strain (strain 2), a different strain (strain 13), or (2 X 13) F1 animals, and the magnitude of T-cell proliferation in response to the antigen-pulsed macrophages was measured.

The results of these experiments, outlined in Figure 8-1, showed that strain-2 antigen-pulsed macrophages activated strain-2 and F1 T cells but not strain-13 T cells. Similarly, strain-13 antigen-pulsed macrophages activated strain-13 and F1 T cells but not strain-2 T cells. Subsequently, congenic and recombinant congenic strains of mice, which differed from each other only in selected regions of the H-2 complex, were used as the source of macrophages and T cells. These experiments confirmed that the CD4+ TH cell is activated and proliferates only in the presence of antigen-pulsed macrophages that share class II MHC alleles. Thus, antigen recognition by the CD4+ TH cell is class II MHC restricted.

In 1974 R. Zinkernagel and P. Doherty demonstrated the self-MHC restriction of CD8+ T cells. In their experiments, mice were immunized with lymphocytic choriomeningitis (LCM) virus; several days later, the animals' spleen cells, which included TC cells specific for the virus, were isolated and incubated with LCM-infected target cells of the same or different haplotype (Figure 8-2). They found that the TC cells killed only syngeneic virus-infected target cells. Later studies with congenic and recombinant congenic strains showed

Peritoneal exudate cells

7 days

Lymph node cells

, /SySySvSv. Adherent cells

Peritoneal macrophages Antigen —.

Antigen-pulsed macrophages

Adherence column (retains macrophages)

Antigen-primed T-cells

Measure T-cell proliferation

Antigen-primed T cell

Antigen-pulsed macrophages

Strain 2

Strain 13

(2 x 13)FX

Strain 2

+

-

+

Strain 13

-

+

+

(2 x 13)F1

+

+

Experimental demonstration of self-MHC restriction of Th cells. Peritoneal exudate cells from strain 2, strain 13, or (2 X 13) F1 guinea pigs were incubated in plastic Petri dishes, allowing enrichment of macrophages, which are adherent cells. The peritoneal macrophages were then incubated with antigen. These "antigen-pulsed" macrophages were incubated in vitro with T cells from strain 2, strain 13, or (2 X 13) F1 guinea pigs, and the degree of T-cell proliferation was assessed. The results indicated that TH cells could proliferate only in response to antigen presented by macrophages that shared MHC alleles. [Adapted from A. Rosenthal and E. Shevach, 1974, J. Exp. Med. 138:1194, by copyright permission of the Rockefeller University Press.]

that the TC cell and the virus-infected target cell must share class I molecules encoded by the K or D regions of the MHC. Thus, antigen recognition by CD8+ TC cells is class I MHC

LCM virus

H-2k

LCM virus

H-2k

Spleen cells (containing Tc cells)

Spleen cells (containing Tc cells)

H-26 LCM-infected target cells

H-2k target cells

H-2k LCM-infected target cells

H-26 LCM-infected target cells

-51Cr release (no lysis)

FIGURE 8-2

+51Cr release (lysis)

-51Cr release (no lysis)

Classic experiment of Zinkernagel and Doherty demonstrating that antigen recognition by TC cells exhibits MHC restriction. H-2k mice were primed with the lymphocytic choriomeningitis (LCM) virus to induce cytotoxic T lymphocytes (CTLs) specific for the virus. Spleen cells from this LCM-primed mouse were then added to target cells of different H-2 haplotypes that were intracellu-larly labeled with 51Cr (black dots) and either infected or not with the LCM virus. CTL-mediated killing of the target cells, as measured by the release of 51Cr into the culture supernatant, occurred only if the target cells were infected with LCM and had the same MHC haplo-type as the CTLs. [Adapted from P. C. Doherty and R. M. Zinkernagel, 1975, J. Exp. Med. 141:502.]

restricted. In 1996, Doherty and Zinkernagel were awarded the Nobel prize for their major contribution to the understanding of cell-mediated immunity.

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