TCR Specificity Dictates CD94/NKG2A Expression by Human CTL

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TCR Specificity Dictates CD94/NKG2A Expression by Human CTL Bana Jabri, Jeanette M Selby, Horia Negulescu, Leanne Lee, Arthur I Roberts, Andrew Beavis, Miguel Lopez-Botet, Ellen C Ebert, Robert J Winchester  Immunity  Volume 17, Issue 4, Pages 487-499 (October 2002) DOI: 10.1016/S1074-7613(02)00427-2

Figure 1 Functional Subsets of CD94+ Memory/Effector CTL According to NKG2 Isotype Expression (A) Freshly isolated IEL and PBL were stained with anti-TCRαβ, anti-CD8, anti-CD94, and anti-NKG2A antibodies to sort CD8+TCRαβ+ with a CD94HighNKG2A+, CD94LowNKG2A−, or CD94− phenotype. Statistical quadrants were set based on isotype control staining (data not shown). (B and C) The pattern of NKG2 isotype expression defined by RT-PCR with NKG2 isotype-specific primers is shown in (B) freshly sorted T-IEL subsets and (C) CD94HighNKG2A+ and CD94HighNKG2A− clones directly derived from the corresponding purified IEL and PBL subsets. (D) The function of CD94 receptors was studied in subsets expressing CD94HighNKG2A+, CD94LowNKG2A−, and CD94/CD94 homodimers using a redirected cytolytic assay of P815 cells in the presence of various doses (10–20 ng/ml) anti-CD3 and 1 μg/ml of anti-CD94 mAb or isotype control (anti-MHC class I mAb). Immunity 2002 17, 487-499DOI: (10.1016/S1074-7613(02)00427-2)

Figure 2 Clonal Composition of CD94HighNKG2A+ and CD94LowNKG2A− Subsets of IEL and PBL (A) Freshly isolated IEL and PBL were stained with anti-CD8, anti-CD94, anti-NKG2A, and a panel of anti-TCRβ BV family-specific antibodies to define BV usage in CD94HighNKG2A+ and CD94LowNKG2A− subsets. All predominant BV families representing 5% or more of the cells are shown. (B) TCR β chain CDR3 length distribution in freshly isolated CD94HighNKG2A+ and CD94LowNKG2A− IEL and PBL. Representative examples illustrate the oligoclonal nature of the TCR repertoires in IEL and PBL. Peaks corresponding to BV12 in IEL and BV13 and BV5 (CDR3 length 10) in PBL were almost exclusively present in the CD94LowNKG2A− population. Conversely, BV18 in IEL and BV6 in PBL were almost exclusively present in the CD94HighNKG2A+population. In contrast, the BV2 peak in IEL and the BV5 (CDR3 length 11) in PBL were present in both the CD94LowNKG2A− and the CD94HighNKG2A+ subsets. BV12 and BV18 IEL peaks correspond to sample D in (A), BV2 in IEL corresponds to sample C, and all PBL peaks correspond to sample P. (C) Summary of the number of oligoclonal expansions found in all BV families in each sample according to their presence in the CD94LowNKG2A− or CD94HighNKG2A+ subset. The Hamming distances (HD) were calculated to compare the repertoires of the CD94LowNKG2A−, the CD94HighNKG2A+, and the reference CD4+ PBL populations for all BV families in all samples studied. HD values range from 0 for identical subsets to 100 for strictly distinct subsets. Immunity 2002 17, 487-499DOI: (10.1016/S1074-7613(02)00427-2)

Figure 3 NKG2A Commitment Revealed by TCR Engagement (A) The CD94LowNKG2A− subset of the Vβ2+ IEL oligoclonal expansion in sample C (shown to be heterogeneous for NKG2A expression in Figures 2A and 2B) was purified and stimulated by anti-CD3. Cell surface NKG2A expression progressively increased until d10 when cells were harvested and rested in the absence of anti-CD3. At d40, NKG2A expression was barely detectable. NKG2A transcripts absent at d0 were induced at d5. (B) Anti-CD3 stimulation was performed to measure the proportion of NKG2A-inducible cells among the CD94LowNKG2A− subsets of samples C and N. (C) Anti-CD3 stimulated clones expressing CD94 homodimers (CD94LowNKG2−), but not clones expressing activating CD94/NKG2C,E receptors, were induced to express NKG2A. Immunity 2002 17, 487-499DOI: (10.1016/S1074-7613(02)00427-2)

Figure 4 Clonal Patterns of NKG2A Expression and Induction in Precommitted Cells The BV4 and BV3 repertoires (β chain length distribution and sequencing) of the CD94LowNKG2A− cells induced to express NKG2A (“NKG2A-induced” sorted 3 days after stimulation with anti-CD3) is shown in (C) for comparison with the repertoires of the original, freshly isolated CD94HighNKG2A+ and CD94LowNKG2A− subsets shown in (A) and (B). Immunity 2002 17, 487-499DOI: (10.1016/S1074-7613(02)00427-2)

Figure 5 CTL Clones Expressing Sequence-Related TCR Exhibit the Same NKG2A Expression Pattern (A) Analysis using β chain length distribution and sequencing of two BV9 oligoclonal expansions of CDR3 length = 9 and 11 shows that each oligoclonal expansion is composed of a group of related sequences. Bolded amino acid residues indicate differences from the reference sequence. The lower portion of the figure contains the nucleotide sequence showing differences in the use of somatic and germline elements. Germline origin is indicated in uppercase, with the D element in bolded italics. Somatic origin is shown in lowercase. (B) β chain sequence analysis of an isolated BV16 oligoclonal expansion of CDR3 length = 10 in freshly purified T cells reveals that the oligoclonal expansion is composed of five related clones. To determine the αβ chain pairing of these clones, the BV16 positive T cells were subcloned and the αβTCR sequences of 17 individual subclones are shown. Immunity 2002 17, 487-499DOI: (10.1016/S1074-7613(02)00427-2)

Figure 6 Model for NKG2A Expression and Function in Effector/Memory CTL (A) Naturally expanded CTL clones expressing related TCR (likely sharing the same antigen specificity) share the same commitment to express NKG2A. Thus, the context in which antigen-specific T cells are primed or expanded during the differentiation process into CD8 effector/memory cells (e.g., the nature of the APC presenting the antigen or the persistent nature of the antigen) determines NKG2A commitment. (B) NKG2A/TCR dominant-negative circuit loop in effector CTL. Surface expression of NKG2A is dependent on TCR stimulation at the effector stage. Resting effector CTL precommitted to the expression of NKG2A express nonfunctional CD94 homodimers. Upon TCR triggering, they express surface CD94/NKG2A. In turn, CD94/NKG2A exerts a negative feedback signal on TCR activation, if it encounters the appropriate HLA-E ligand. This negative feedback may be an important mechanism to prevent chronic inflammation and autoimmunity in an environment of high antigenic load such as the intestine. Immunity 2002 17, 487-499DOI: (10.1016/S1074-7613(02)00427-2)