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The route of antigen entry determines the requirement for L-selectin during immune responses.

Catalina MD, Carroll MC, Arizpe H, Takashima A, Estess P, Siegelman MH - J. Exp. Med. (1996)

Bottom Line: Thus, antigen presentation and effector mechanisms are intact in L-selectin deficient mice.In contrast, virtually no antigen-specific T cells can be found within draining peripheral nodes after a contact challenge, suggesting that the defect resides primarily in the inability of antigen-specific T cells to home to and be activated in these nodes.These studies pinpoint the lesion in CHS to a discrete stage of the afferent limb of the response, clarify the role of L-selectin on effector populations, and illustrate the critical importance of the route of antigen entry to the successful execution of an immune response.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas 75235-9072, USA.

ABSTRACT
L-selectin, an adhesion molecule constitutively expressed on leukocytes, is important for primary adhesion and extravasation of lymphocytes at specialized high endothelial venules within lymph nodes and other leukocytes at sites of inflammation. We have generated L-selectin-deficient mice by targeted disruption, and have confirmed a previously reported phenotype which includes strikingly impaired contact hypersensitivity (CHS) responses to reactive haptens (Tedder, T.F., D.A. Steeber, and P. Pizcueta. 1995. J. Exp. Med. 181:2259-2264; Xu, J.C., I.S. Grewal, G.P. Geba, and R.A. Flavell. 1996. 183:589-598.). Since the mechanism of this impairment has not been clarified, we sought to define the stage(s) at which the CHS response is affected in L-selectin-deficient mice. We show that epidermal Langerhans cells in L-selectin-deficient mice are normal in number, migrate to peripheral lymph nodes appropriately, and are functional in presenting allogeneic and haptenic antigens. Moreover, T cells, as well as neutrophil and monocyte effector populations, are fully capable of entry into the inflamed skin sites in the absence of L-selectin. Thus, antigen presentation and effector mechanisms are intact in L-selectin deficient mice. In contrast, virtually no antigen-specific T cells can be found within draining peripheral nodes after a contact challenge, suggesting that the defect resides primarily in the inability of antigen-specific T cells to home to and be activated in these nodes. Indeed, L-selectin-deficient mice mount completely normal CHS responses when alternate routes of immunization are used. These studies pinpoint the lesion in CHS to a discrete stage of the afferent limb of the response, clarify the role of L-selectin on effector populations, and illustrate the critical importance of the route of antigen entry to the successful execution of an immune response.

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(A) L-selectin–deficient mice have impaired CHS responses  to DNFB, oxazolone, and FITC. Wild-type mice sensitized and elicited  had significantly greater ear swelling than the sensitized and elicited L-selectin–deficient mice (*; P <0.05) and significantly greater ear swelling than  both wild-type and L-selectin–deficient elicited-only mice (*; P <0.05).  There was no significant difference between the response of L-selectin– deficient mice which were both sensitized and elicited, and either wildtype or L-selectin–deficient mice which were elicited only for any of the  tested haptens (P >0.5). Results shown are the change in ear thickness at 24 h  from mice elicited with CHS reagent on days 5 (DNFB), 6 (FITC), or 7  (oxazolone). n values are given in parentheses. (B) Delay of challenge  with either DNFB or oxazolone does not restore the ability of L-selectin– deficient mice to respond to CHS agents. Wild-type mice sensitized and  elicited had significantly greater ear swelling than the sensitized and elicited L-selectin–deficient mice when mice were challenged 9 d after sensitization for DNFB or 12 d after sensitization for oxazolone (*; P <0.05).  There was no significant difference between the response of sensitized  and elicited L-selectin–deficient mice and mice which were elicited only  (P >0.5).
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Figure 2: (A) L-selectin–deficient mice have impaired CHS responses to DNFB, oxazolone, and FITC. Wild-type mice sensitized and elicited had significantly greater ear swelling than the sensitized and elicited L-selectin–deficient mice (*; P <0.05) and significantly greater ear swelling than both wild-type and L-selectin–deficient elicited-only mice (*; P <0.05). There was no significant difference between the response of L-selectin– deficient mice which were both sensitized and elicited, and either wildtype or L-selectin–deficient mice which were elicited only for any of the tested haptens (P >0.5). Results shown are the change in ear thickness at 24 h from mice elicited with CHS reagent on days 5 (DNFB), 6 (FITC), or 7 (oxazolone). n values are given in parentheses. (B) Delay of challenge with either DNFB or oxazolone does not restore the ability of L-selectin– deficient mice to respond to CHS agents. Wild-type mice sensitized and elicited had significantly greater ear swelling than the sensitized and elicited L-selectin–deficient mice when mice were challenged 9 d after sensitization for DNFB or 12 d after sensitization for oxazolone (*; P <0.05). There was no significant difference between the response of sensitized and elicited L-selectin–deficient mice and mice which were elicited only (P >0.5).

Mentions: Because of the multiple sites at which L-selectin can contribute, CHS responses were used to examine the functional significance of the loss of L-selectin expression. These mice show markedly impaired CHS responses to each of the tested haptens DNFB, oxazolone, and FITC (Fig. 2 A). It is also of interest that the response of sensitized heterozygous mice to DNFB was not significantly different from the response of wild-type mice (Fig. 2 A), despite less effective adhesion under shear forces. The extent of ear swelling is comparable among sensitized mutant mice, nonsensitized mutant mice, and nonsensitized wild-type mice, suggesting that no substantial antigen-specific element to the response was present in L-selectin–deficient mice. In contrast, while hapten-specific responses are blunted in L-selectin–deficient mice, the nonspecific irritant response, different for each hapten, remains intact in mutant animals (see below). Moreover, the irritant effect is not due to vehicle since both DNFB and oxazolone, each with different irritant effects, are applied in the same vehicle.


The route of antigen entry determines the requirement for L-selectin during immune responses.

Catalina MD, Carroll MC, Arizpe H, Takashima A, Estess P, Siegelman MH - J. Exp. Med. (1996)

(A) L-selectin–deficient mice have impaired CHS responses  to DNFB, oxazolone, and FITC. Wild-type mice sensitized and elicited  had significantly greater ear swelling than the sensitized and elicited L-selectin–deficient mice (*; P <0.05) and significantly greater ear swelling than  both wild-type and L-selectin–deficient elicited-only mice (*; P <0.05).  There was no significant difference between the response of L-selectin– deficient mice which were both sensitized and elicited, and either wildtype or L-selectin–deficient mice which were elicited only for any of the  tested haptens (P >0.5). Results shown are the change in ear thickness at 24 h  from mice elicited with CHS reagent on days 5 (DNFB), 6 (FITC), or 7  (oxazolone). n values are given in parentheses. (B) Delay of challenge  with either DNFB or oxazolone does not restore the ability of L-selectin– deficient mice to respond to CHS agents. Wild-type mice sensitized and  elicited had significantly greater ear swelling than the sensitized and elicited L-selectin–deficient mice when mice were challenged 9 d after sensitization for DNFB or 12 d after sensitization for oxazolone (*; P <0.05).  There was no significant difference between the response of sensitized  and elicited L-selectin–deficient mice and mice which were elicited only  (P >0.5).
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Figure 2: (A) L-selectin–deficient mice have impaired CHS responses to DNFB, oxazolone, and FITC. Wild-type mice sensitized and elicited had significantly greater ear swelling than the sensitized and elicited L-selectin–deficient mice (*; P <0.05) and significantly greater ear swelling than both wild-type and L-selectin–deficient elicited-only mice (*; P <0.05). There was no significant difference between the response of L-selectin– deficient mice which were both sensitized and elicited, and either wildtype or L-selectin–deficient mice which were elicited only for any of the tested haptens (P >0.5). Results shown are the change in ear thickness at 24 h from mice elicited with CHS reagent on days 5 (DNFB), 6 (FITC), or 7 (oxazolone). n values are given in parentheses. (B) Delay of challenge with either DNFB or oxazolone does not restore the ability of L-selectin– deficient mice to respond to CHS agents. Wild-type mice sensitized and elicited had significantly greater ear swelling than the sensitized and elicited L-selectin–deficient mice when mice were challenged 9 d after sensitization for DNFB or 12 d after sensitization for oxazolone (*; P <0.05). There was no significant difference between the response of sensitized and elicited L-selectin–deficient mice and mice which were elicited only (P >0.5).
Mentions: Because of the multiple sites at which L-selectin can contribute, CHS responses were used to examine the functional significance of the loss of L-selectin expression. These mice show markedly impaired CHS responses to each of the tested haptens DNFB, oxazolone, and FITC (Fig. 2 A). It is also of interest that the response of sensitized heterozygous mice to DNFB was not significantly different from the response of wild-type mice (Fig. 2 A), despite less effective adhesion under shear forces. The extent of ear swelling is comparable among sensitized mutant mice, nonsensitized mutant mice, and nonsensitized wild-type mice, suggesting that no substantial antigen-specific element to the response was present in L-selectin–deficient mice. In contrast, while hapten-specific responses are blunted in L-selectin–deficient mice, the nonspecific irritant response, different for each hapten, remains intact in mutant animals (see below). Moreover, the irritant effect is not due to vehicle since both DNFB and oxazolone, each with different irritant effects, are applied in the same vehicle.

Bottom Line: Thus, antigen presentation and effector mechanisms are intact in L-selectin deficient mice.In contrast, virtually no antigen-specific T cells can be found within draining peripheral nodes after a contact challenge, suggesting that the defect resides primarily in the inability of antigen-specific T cells to home to and be activated in these nodes.These studies pinpoint the lesion in CHS to a discrete stage of the afferent limb of the response, clarify the role of L-selectin on effector populations, and illustrate the critical importance of the route of antigen entry to the successful execution of an immune response.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas 75235-9072, USA.

ABSTRACT
L-selectin, an adhesion molecule constitutively expressed on leukocytes, is important for primary adhesion and extravasation of lymphocytes at specialized high endothelial venules within lymph nodes and other leukocytes at sites of inflammation. We have generated L-selectin-deficient mice by targeted disruption, and have confirmed a previously reported phenotype which includes strikingly impaired contact hypersensitivity (CHS) responses to reactive haptens (Tedder, T.F., D.A. Steeber, and P. Pizcueta. 1995. J. Exp. Med. 181:2259-2264; Xu, J.C., I.S. Grewal, G.P. Geba, and R.A. Flavell. 1996. 183:589-598.). Since the mechanism of this impairment has not been clarified, we sought to define the stage(s) at which the CHS response is affected in L-selectin-deficient mice. We show that epidermal Langerhans cells in L-selectin-deficient mice are normal in number, migrate to peripheral lymph nodes appropriately, and are functional in presenting allogeneic and haptenic antigens. Moreover, T cells, as well as neutrophil and monocyte effector populations, are fully capable of entry into the inflamed skin sites in the absence of L-selectin. Thus, antigen presentation and effector mechanisms are intact in L-selectin deficient mice. In contrast, virtually no antigen-specific T cells can be found within draining peripheral nodes after a contact challenge, suggesting that the defect resides primarily in the inability of antigen-specific T cells to home to and be activated in these nodes. Indeed, L-selectin-deficient mice mount completely normal CHS responses when alternate routes of immunization are used. These studies pinpoint the lesion in CHS to a discrete stage of the afferent limb of the response, clarify the role of L-selectin on effector populations, and illustrate the critical importance of the route of antigen entry to the successful execution of an immune response.

Show MeSH
Related in: MedlinePlus