Indirect Minor Histocompatibility Antigen Presentation by Allograft Recipient Cells in the Draining Lymph Node Leads to the Activation and Clonal Expansion of CD4+ T Cells That Cause Obliterative Airways Disease

Abstract

Ag recognition by OVA-reactive OT-II (I-Ab restricted) and DO11.10 (I-Ad restricted) TCR-Tg CD4+ T cells after heterotopic transplantation of OVA transgene-expressing tracheal grafts was examined as a model of minor histocompatibility Ag (mHAg)-induced chronic allograft rejection. In response to airway allotransplantation with grafts expressing the OVA transgene, these TCR-Tg CD4+ T cells expressed the activation markers CD69 and CD44, demonstrated evidence of blastogenesis, underwent multiple rounds of cell division leading to their clonal expansion in the draining lymph node, and proceeded to differentiate to a effector/memory T cell phenotype based on a reduction in the expression of CD45RB. These mHAg-specific TCR-Tg CD4+ T cells responded equally well to fully MHC-mismatched tracheas and to class II-deficient allografts, demonstrating that donor mHAg recognition by recipient CD4+ T cells does not rely on Ag presentation by donor-derived APC. The activation of mHAg-specific TCR-Tg CD4+ T cells after their adoptive transfer into recipient mice given MHC-matched, but mHAg-disparate, airway allografts was associated with their movement into the allograft and the near uniform destruction of the transplanted airway tissue secondary to the development of obliterative airways disease. These results demonstrate that an activation of mHAg-reactive CD4+ T cells in the draining lymph node by recipient APC that indirectly express graft mHAg-derived peptide/class II MHC complexes precedes responder T cell proliferation and differentiation, and leads to the eventual migration of these alloreactive T cells to the transplanted airway tissue and the promotion of chronic graft rejection.

A Human-Mouse Chimeric Model of Obliterative Bronchiolitis after Lung Transplantation

“…Moreover, the generation of OB among recipients of pure CD4 T-cell inocula here, as well as analogous findings in other murine model systems 6,7,33 illustrates the pathogenic potential of isolated T-cell subpopulations. Thus, the present studies corroborate and extend previous experimental findings that implicate the critical dependence of T-cell alloresponses in the development of OB.…”

“…A novel and potentially important feature of this model is that both the immune effector cells and the allograft target are of human derivation, and thus are singularly relevant to studies of pathogenic processes that occur in human lung transplant patients. Although useful information has been and will continue to be gleaned from traditional studies of airway and other transplantations among allogeneic mouse strains, [3][4][5][6][7] there are a considerable number of differences between mouse and human immune systems. 8,9 As one of many examples, oligoclonal daughter progeny of human T cells that have undergone repetitive, antigen-driven proliferations develop markedly dysregulated and pathogenic characteristics and functions, including increased expression of NK-cell receptors, absence of cell-surface CD28, discordant expression of many activation and maturation markers, telomere shortening, and diminished production of FoxP3.…”

“…The operating characteristics of this system were therefore defined in the absence of immunosuppressive treatments, to minimize the number and complexity of experimental variables, with the net result that differences of HAG appearance between the control and immune-reconstituted recipients occurred rapidly and were striking. A similar approach was adopted in development and description of the murine heterotopic airway model, 4 which has since seen wide use, [5][6][7]33 as well as in the development of other animal models used to study the immunobiology of transplantation. 3 Although not tested here, we hypothesize that treatment of experimental animals with effective immunosuppressants, to recreate conditions in human allograft recipients, could have a measurable effect on the development of OB (for example, it might slow the progression or extent of airway pathology).…”

“…3 With particular respect to pulmonary transplantation, heterotopic tracheal allografts in mice undergo histological abnormalities that reproduce the progression of OB in humans, including an initial lymphocytic infiltration, followed by successive stages of epithelial metaplasia and denudation and, ultimately, intraluminal fibroproliferation. [3][4][5][6][7] Although this model successfully recapitulates the histological abnormalities of OB, the system is limited to study of nonhuman immune effector cells and airways.Mice and humans diverged approximately 70 million years ago, however, and have since evolved striking differences of size, reproductive capability, longevity, diet, and habitat, as well as having varied exposures to particular microbial and viral pathogens. 8 All of these factors, and doubtless others, have exerted idiosyncratic selection pressures on the evolution of the respective host defense mechanisms.…”

“…3 With particular respect to pulmonary transplantation, heterotopic tracheal allografts in mice undergo histological abnormalities that reproduce the progression of OB in humans, including an initial lymphocytic infiltration, followed by successive stages of epithelial metaplasia and denudation and, ultimately, intraluminal fibroproliferation. [3][4][5][6][7] Although this model successfully recapitulates the histological abnormalities of OB, the system is limited to study of nonhuman immune effector cells and airways.…”