I region‐restricted T cell line stimulated with haptentreated syngeneic cells: Selection of clones with reactivity for both allogeneic Ia determinants and self‐I‐A plus hapten

Abstract

The apparent switch in proliferative T cell reactivity which occurred in a B10 T cell line (B10(T4)) repeatedly stimulated with trinitrobenzene sulfonic acid (hapten)-treated syngeneic cells is described. This functionally heterogenous T cell population, apparently depleted of alloreactivity and strictly dependent on cells expressing syngeneic I-A and the hapten for its propagation, lost, after its 10th restimulation, the previously detected T cell functions, and expressed a new pattern of proliferative reactivity; this pattern included reactivity to self-I-A plus hapten as well as to untreated stimulating cells expressing certain allogeneic determinants. Analysis of reactivity of B10(T4) cells grown under limiting dilution conditions and of five clones of cells derived from B10(T4) indicated that the same T cells were reactive to both self-I-A plus hapten, and to a public I-A-mapped alloantigen possibly related to the serologically defined Ia.5 specificity.

Early development of the T cell repertoire. In vivo treatment of neonatal mice with anti-Ia antibodies interferes with differentiation of I-restricted T cells but not K/D-restricted T cells.

“…First, allo-Ia-specific T helper cells might in fact all be specific for self-I-A plus conventional antigen, so that they require intrathymic Ia education, which has been disturbed in these mice. Reports that several self-I-A plus antigenspecific T cell clones and hybridomas (36)(37)(38) were cross-reactive with allogeneic I-A determinants support this notion. Second, the generation of allo-K/D region-specific CTL responses might require presentation of the allogeneic determinants in the context of self-Ia allogeneic determinants (39,40), but self-Ia-restricted T helper cells are incompetent in these mice.…”

Alloreactivity: An Old Puzzle Revisited

“…Parallel with the theoretical efforts, experimental results generated by Bevan [19] and Benacerraf’s group [20, 21] demonstrated that T cells activated against a foreign antigen plus self‐MHC indeed cross‐reacted with allogeneic MHC molecules in the absence of the foreign antigen. Subsequently, these findings were confirmed at the level of individual T cell clones in a number of reports [22–26]. Thus, alloreactivity has been proven to be an inherent property of the self‐MHC restricted T cell repertoire, instead of being mediated by a useless subset of T cells.…”

“…Implicit in these statements is that the repertoire before negative selection should have TCRs with high affinity and extensive cross‐reactivity, and indeed this has been shown to be the case in a repertoire that underwent limited negative selection [63]. Similarly, in alloreactivity, TCRs can be identified with affinities that are higher than the affinity for foreign peptide plus self‐MHC [58, 64, 65], and extensive cross‐reactivity with multiple allelic variants of MHC molecules is also commonly found [25, 26, 55, 56].…”

“…Further studies have added more mechanistic details as to how certain T cell clones achieve alloreactivity. For example, many self‐restricted antigen‐specific clones, once alloreactive, were shown to react to multiple allogeneic MHC molecules [25, 26, 55, 56]. Thus, extensive cross‐reactivity, also at the clonal level, seems to be a rule rather than exception in alloreactivity.…”

The Cytotoxic T‐Cell Response to la Antigens: Lack of Correlation between the Level of Specific Cytotoxicity Obtained in Primary Mixed Lymphocyte Reaction and the Frequency of Specific Cytotoxic T Lymphocyte

“…However, a clear distinction between the two sets of the repertoire cannot be made, since K and D regions have been shown to control strong mixed lymphocyte reactions (MLR) [11] and to mediate T||-B cell cooperation [2 (1, 17i. It has also been shown by different authors [10,12,16,21 [ that allogeneic class II antigen.s can elicit strong cytotoxic responses in unprimed animals, as would be the case if the number of precursors specific for ia antigens was at least of the same order of magnitude as that of class I specific CTL precursors (CTLp). However, this type of itnmune response seems to be directed mostly against allogeneic H-2 antigens, since no antigen-specific and larestricted CTL have, to otir knowledge, been described, with the exception of some alloreactive Ia-spccific CTL clones that were found to crossreact with haptenated syngeneic cells [6].…”