Protective immunity against malaria is induced by vaccination of hosts with irradiation-attenuated sporozoites. This immunity is mediated in part by neutralizing antibodies that are directed mainly against the repeat domain of the circumsporozoite protein. Early experiments showed, however, that B-cell-depleted mice that are immunized with sporozoites can resist challenge, indicating that T-cell effector mechanisms may also have a role in protection. This idea was supported by the recent observation that protective immunity also requires T-cells expressing the CD8 antigen (CD8+ T cells) whose target is probably the developing liver-stage parasites. Moreover, an oral Salmonella vaccine that expresses the circumsporozoite protein is able to protect against murine malaria in the absence of antibodies. Here we report the identification of an epitope contained within amino acids 249-260 of the Plasmodium berghei circumsporozoite protein that is recognized by H-2Kd-restricted cytotoxic T cells. Passive transfer into mice of cytotoxic-T-cell clones that recognize this epitope conferred a high degree of protection against challenge. These results provide the first direct evidence that CD8+ T cells that are specific for a defined epitope can confer protection against a parasitic infection.

The first checkpoint during T cell development, known as β selection, requires the successful rearrangement of the TCR-β gene locus. Notch signaling has been implicated in various stages during T lymphopoiesis. However, it is unclear whether Notch receptor-ligand interactions are necessary during β selection. Here, we show that pre-TCR signaling concurrent with Notch receptor and Delta-like-1 ligand interactions are required for the survival, proliferation, and differentiation of mouse CD4−CD8− thymocytes to the CD4+CD8+ stage. Furthermore, we address the minimal signaling requirements underlying β selection and show a hierarchical positioning of key proximal signaling molecules. Collectively, our results demonstrate an essential role for Notch receptor-ligand interactions in enabling the autonomous signaling capacity of the pre-TCR complex.

SummaryWe report here the first extensive study ofa T cell repertoire for a class I major histocompatibility complex (MHC)-restricted cytotoxic T lymphocyte (CTL) response. We have found that the T cell receptors (TCRs) carried by 28 H-2Ka-restricted CTL clones specific for a single Plasmodium berghei circumsporozoite nonapeptide are highly diverse in terms of Vg Jot, and JB segments and aminoacid composition of the junctional regions. However, despite this extensive diversity, a high proportion of the TCRs contain the same V~8 segment. These results are in contrast to most previously reported T cell responses towards class II MHC-peptide complexes, where the TCR repertoires appeared to be much more limited. In our study, the finding of a dominant V/~ in the midst of otherwise highly diverse TCRs suggests the importance of the VB segment in shaping the T cell repertoire specific for a given MHC-peptide complex. As an additional finding, we observed that nearly all clones have rearranged both TCR ot loci. Moreover, as many as one-third of the CTL clones that we analyzed apparently display two productive ot rearrangements. This argues against a regulated model of sequential recombination at the ot locus and consequently raises the question of whether allelic exclusion of the TCR ot chain is achieved at all.T he mouse TCR ot/~ is a disulphide-linked heterodimeric integral membrane glycoprotein. Each chain of •40-45 kD contains a C and a V extracellular domain (1). The diversity of each ot and B V domain results from the somatic recombination of ",,100 Va with "~50 joining ot (Jot) gene segments and of '~20 V/5 with two diversity fl (DE) and 12joining B (J~0) gene segments, respectively. Imprecise joining and addition of template-independent N-nucleotides further contribute to this diversity (2). The TCR is closely related to Ig by similar domain organization, overall sequence homology, and conservation of key residues. Along this line, Chothia et al. (3) have proposed an outline of the TCR tertiary structure, based on the known three-dimensional structure of Igs.Whereas B cells recognize epitopes on native antigenic proteins, T cells can only recognize antigens in the context of cell surface syngeneic MHC molecules (4). The antigens recognized by T cells can be mimicked by synthetic peptides (5). The crystallographic structure of two class I MHC molecules has revealed a groove in the external domain, where the antigenic peptide could lie (6-8). There is now evidence that the antigens are naturally processed into short peptides that are loaded onto MHC molecules and exported at the cell surface (9-11).The T cell specificity for an MHC-peptide complex is determined exclusively by the TCR (12). Accordingly, one question has received much attention. What is the diversity of the TCR.s carried by T cells of a given specificity?The determination of the primary structure of a number of TCKs carried by T cell clones or hybridomas of a given specificity, mostly MHC class II restricted, has been performed for a variety of pro...

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